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1
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Golyako IA, Kuzmin VS, Gorbacheva LR. The effect of hyperglycemia on the activation of peritoneal macrophages of albino rats. BIOMEDITSINSKAIA KHIMIIA 2023; 69:394-402. [PMID: 38153054 DOI: 10.18097/pbmc20236906394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2023]
Abstract
Hyperglycemia is one of the main damaging factors of diabetes mellitus (DM). The severity of this disease is most clearly manifested under conditions of the inflammatory process. In this work, we have studied the activation features of rat peritoneal macrophages (MPs) under conditions of high glucose concentration in vitro. Comparison of the independent and combined effects of streptozotocin-induced DM and hyperglycemia on proliferation and accumulation of nitrites in the MPs culture medium revealed similarity of their effects. Elevated glucose levels and, to a lesser extent, DM decreased basal proliferation and NO production by MPs in vitro. The use of the protein kinase C (PKC) activator, phorbol ester (PMA), abolished the proinflammatory effect of thrombin on PMs. This suggests the involvement of PKC in the effects of the protease. At the same time, the effect of thrombin on the level of nitrites in the culture medium demonstrates a pronounced dose-dependence, which was not recognized during evaluation of proliferation. Proinflammatory activation of MPs is potentiated by hyperglycemia, one of the main pathological factors of diabetes. Despite the fact that high concentrations of glucose have a significant effect on proliferation and NO production, no statistically significant differences were found between the responses of MPs obtained from healthy animals and from animals with streptozotocin-induced DM. This ratio was observed for all parameters studied in the work, during analysis of cell proliferation and measurement of nitrites in the culture medium. Thus, the results obtained indicate the leading role of elevated glucose levels in the regulation of MPs activation, which is comparable to the effect of DM and even "masks" it.
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Affiliation(s)
| | - V S Kuzmin
- Academician E.I. Chazov National Medical Research Center for Cardiology, Moscow, Russia
| | - L R Gorbacheva
- Moscow State University, Moscow, Russia; Pirogov Russian National Research Medical University, Moscow, Russia
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2
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Upregulation of microRNA-532 enhances cardiomyocyte apoptosis in the diabetic heart. Apoptosis 2021; 25:388-399. [PMID: 32418060 DOI: 10.1007/s10495-020-01609-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Type 2 diabetes has a strong association with the development of cardiovascular disease, which is grouped as diabetic heart disease (DHD). DHD is associated with the progressive loss of cardiovascular cells through the alteration of molecular signalling pathways associated with cell death. In this study, we sought to determine whether diabetes induces dysregulation of miR-532 and if this is associated with accentuated apoptosis. RT-PCR analysis showed a significant increase in miR-532 expression in the right atrial appendage tissue of type 2 diabetic patients undergoing coronary artery bypass graft surgery. This was associated with marked downregulation of its anti-apoptotic target protein apoptosis repressor with caspase recruitment domain (ARC) and increased TUNEL positive cardiomyocytes. Further analysis showed a positive correlation between apoptosis and miR-532 levels. Time-course experiments in a mouse model of type 2 diabetes showed that diabetes-induced activation of miR-532 occurs in the later stage of the disease. Importantly, the upregulation of miR-532 preceded the activation of pro-apoptotic caspase-3/7 activity. Finally, inhibition of miR-532 activity in high glucose cultured human cardiomyocytes prevented the downregulation of ARC and attenuated apoptotic cell death. Diabetes induced activation of miR-532 plays a critical role in accelerating cardiomyocytes apoptosis. Therefore, miR-532 may serve as a promising therapeutic agent to overcome the diabetes-induced loss of cardiomyocytes.
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Lu CH, Ou HC, Day CH, Chen HI, Pai PY, Lee CY, Chen RJ, Chang RL, PadmaViswanadha V, Hsieh DJY, Huang CY. Deep sea minerals ameliorate diabetic-induced inflammation via inhibition of TNFα signaling pathways. ENVIRONMENTAL TOXICOLOGY 2020; 35:468-477. [PMID: 31794124 DOI: 10.1002/tox.22882] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 10/25/2019] [Accepted: 11/03/2019] [Indexed: 06/10/2023]
Abstract
It has been well-documented that the consumption of deep sea water (DSW) has beneficial effects on myocardial hypertrophy and cardiac apoptosis induced by hypercholesterolemia. However, the molecular mechanisms for the anti-inflammatory effects of DSW on diabetic cardiomyopathy are still largely unclear. The main purpose of this present study was to test the hypothesis that DSW exerts anti-inflammatory effects through the suppression of the TNF-α-mediated signaling pathways. IP injection of streptozotocin (STZ) at the dose of 65 mg/kg was used to establish a diabetes rat model. DSW mineral extracts that diluted in desalinated water were prepared in three different dosages and administered to the rats through gavages for 4 weeks. These dosages are DSW-1X (equivalent to 37 mg Mg2+ /kg/day), 2X (equivalent to 74 mg Mg2+ /kg/day) and 3X (equivalent to 111 mg Mg2+ mg/kg/day). Immunofluorescence staining and Western blot showed that the protein expression level of TNF-α was markedly higher in the STZ-induced diabetic rat hearts than in the control group. Consequently, the phosphorylation levels of the TNF-α-modulated downstream signaling molecules and P38 mitogen-activated protein kinases (MAPKs) were notably elevated in heart tissues of STZ-induced diabetes. These higher phosphorylation levels subsequently upregulated NF-κB-modulated inflammatory mediators, such as cyclooxygenase (COX)-II and inducible nitric oxide synthase (iNOS). However, treatment with DSW as well as MgSO4 , the main mineral in DSW, significantly reversed all the alterations. These findings suggest that DSW has potential as a therapeutic agent for preventing diabetes-related cardiovascular diseases.
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Affiliation(s)
- Chieh-Hsiang Lu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
| | - Hsiu-Chung Ou
- Department of Physical Therapy, College of Medical and Health Science, Asia University, Taichung, Taiwan
| | | | - Hsiu-I Chen
- Department of Physical Therapy, Hungkuang University, Taichung, Taiwan
| | - Pei-Ying Pai
- School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
- Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Cheng-Yu Lee
- Department of Cardiology, Taipei City Hospital, Zhongxiao Branch, Taipei, Taiwan
| | - Ray-Jade Chen
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Ruey-Lin Chang
- School of Post-Baccalaureate Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
| | | | - Dennis Jine-Yuan Hsieh
- School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
- Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Chih-Yang Huang
- Graduate Institute of Biomedicine, China Medical University and Hospital, Taichung, Taiwan
- Department of Biotechnology, Asia University, Taichung, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
- Cardiovascular and Mitochondrial Related Diseases Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien, Taiwan
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Pang X, Lin X, Du J, Zeng D. LTBP2 knockdown by siRNA reverses myocardial oxidative stress injury, fibrosis and remodelling during dilated cardiomyopathy. Acta Physiol (Oxf) 2020; 228:e13377. [PMID: 31512380 DOI: 10.1111/apha.13377] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 08/19/2019] [Accepted: 09/05/2019] [Indexed: 12/13/2022]
Abstract
AIM Dilated cardiomyopathy (DCM) is characterised by left ventricular dilation and associated with systolic dysfunction. Recent evidence has reported the high expression of latent transforming growth factor beta binding protein 2 (LTBP2) in heart diseases, which may play a role in regulating multiple biological functions of myocardial cells. Thus, this study set out to investigate the molecular mechanism and effects of LTBP2 in myocardial oxidative stress injury, fibrosis and remodelling in a rat model of DCM, with the involvement of NF-κB signalling pathway. METHODS The rat model of DCM was treated with si-LTBP2 and/or activator of NF-κB signalling pathway to examine the haemodynamic indexes, cardiac functions, oxidative stress injury, fibrosis and remodelling. Moreover, in vitro experiments were conducted to verify the regulatory role of LTBP2 and NF-κB signalling pathway in DCM. RESULTS LTBP2 was up-regulated in DCM rats. After LTBP2 was knocked down, haemodynamic indexes, HW/BW ratio, collagen volume fraction (CVF) level, positive expression of LTBP2, levels of reactive oxygen species (ROS), malondialdehyde (MDA), interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α), tumour necrosis factor beta 1 (TGF-β1) and brain natriuretic peptide (BNP) were all decreased. Meanwhile, levels of LTBP2, Col-I, Col-III, p65 and p52 were also reduced, while HW, BW and levels of SOD and TAOC were increased. In contrast, activation of NF-κB signalling pathway reversed effects of LTBP2 gene silencing. These findings were confirmed by in vivo experiments. CONCLUSIONS LTBP2 silencing can attenuate myocardial oxidative stress injury, myocardial fibrosis and myocardial remodelling in DCM rats by down-regulating the NF-κB signalling pathway.
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Affiliation(s)
- Xue‐Feng Pang
- Department of Cardiovascular The First Hospital of China Medical University Shenyang China
| | - Xue Lin
- Department of Cardiovascular Peking Union Medical College Hospital Beijing China
| | - Jian‐Jun Du
- Department of Cardiovascular The First Hospital of China Medical University Shenyang China
| | - Ding‐Yin Zeng
- Department of Cardiovascular The First Hospital of China Medical University Shenyang China
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Contribution of Impaired Insulin Signaling to the Pathogenesis of Diabetic Cardiomyopathy. Int J Mol Sci 2019; 20:ijms20112833. [PMID: 31212580 PMCID: PMC6600234 DOI: 10.3390/ijms20112833] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 06/06/2019] [Accepted: 06/07/2019] [Indexed: 12/19/2022] Open
Abstract
Diabetic cardiomyopathy (DCM) has emerged as a relevant cause of heart failure among the diabetic population. Defined as a cardiac dysfunction that develops in diabetic patients independently of other major cardiovascular risks factors, such as high blood pressure and coronary artery disease, the underlying cause of DCMremains to be unveiled. Several pathogenic factors, including glucose and lipid toxicity, mitochondrial dysfunction, increased oxidative stress, sustained activation of the renin-angiotensin system (RAS) or altered calcium homeostasis, have been shown to contribute to the structural and functional alterations that characterize diabetic hearts. However, all these pathogenic mechanisms appear to stem from the metabolic inflexibility imposed by insulin resistance or lack of insulin signaling. This results in absolute reliance on fatty acids for the synthesis of ATP and impairment of glucose oxidation. Glucose is then rerouted to other metabolic pathways, with harmful effects on cardiomyocyte function. Here, we discuss the role that impaired cardiac insulin signaling in diabetic or insulin-resistant individuals plays in the onset and progression of DCM.
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Tang X, Zhong J, Zhang H, Luo Y, Liu X, Peng L, Zhang Y, Qian X, Jiang B, Liu J, Li S, Chen Y. Visit-to-visit fasting plasma glucose variability is an important risk factor for long-term changes in left cardiac structure and function in patients with type 2 diabetes. Cardiovasc Diabetol 2019; 18:50. [PMID: 30992008 PMCID: PMC6469221 DOI: 10.1186/s12933-019-0854-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 04/05/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND To investigate the effect of visit-to-visit fasting plasma glucose (FPG) variability on the left cardiac structure and function in patients with type 2 diabetes mellitus (T2DM). METHODS In this prospective cohort study, 455 T2DM patients were included and follow-up for a median of 4.7 years. FPG measured on every hospital visit was collected. FPG variability was calculated by its coefficient of variation (CV-FPG). Left cardiac structure and function were assessed using echocardiography at baseline and after follow-up. Multivariable linear regression analyses were used to estimate the effect of FPG variability on the annualized changes in left cardiac structure and function. Subgroup analysis stratified by mean HbA1c levels (< 7% and ≥ 7%) were also performed. RESULT In multivariable regression analyses, CV-FPG was independently associated with the annualized changes in left ventricle (β = 0.137; P = 0.031), interventricular septum (β = 0.215; P = 0.001), left ventricular posterior wall thickness (β = 0.129; P = 0.048), left ventricular mass index (β = 0.227; P < 0.001), and left ventricular ejection fraction (β = - 0.132; P = 0.030). After additionally stratified by mean HbA1c levels, CV-FPG was still independently associated with the annualized changes in the above parameters in patients with HbA1c ≥ 7%, while not in patients with HbA1c < 7%. CONCLUSIONS Visit-to-visit variability in FPG could be a novel risk factor for the long-term adverse changes in left cardiac structure and systolic function in patients with type 2 diabetes. Trial registration ClinicalTrials.gov (NCT02587741), October 27, 2015, retrospectively registered.
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Affiliation(s)
- Xixiang Tang
- Department of Endocrinology & Metabosim, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China.,Advanced Medical Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Junlin Zhong
- Department of Ultrasonography, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Hui Zhang
- Department of Ultrasonography, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Yanting Luo
- Department of Cardiology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Xing Liu
- Department of Cardiology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Long Peng
- Department of Cardiology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Yanling Zhang
- Department of Ultrasonography, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Xiaoxian Qian
- Department of Cardiology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Boxiong Jiang
- Advanced Medical Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Jinlai Liu
- Department of Cardiology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Suhua Li
- Department of Cardiology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China.
| | - Yanming Chen
- Department of Endocrinology & Metabosim, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China.
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Louis XL, Raj P, McClinton KJ, Yu L, Suh M, Netticadan T. Supplementation of Type 1 Diabetic Rats with Carrot Powder Lowers Blood Glucose without Improving Cardiac Structure and Function. Prev Nutr Food Sci 2018; 23:115-121. [PMID: 30018889 PMCID: PMC6047871 DOI: 10.3746/pnf.2018.23.2.115] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 04/05/2018] [Indexed: 01/17/2023] Open
Abstract
Foods and food bioactives have shown to be effective in preventing some human disease conditions. In this study, we examined the effects of carrot powder, rich in carotenoids, as a dietary supplement for the prevention of cardiac anomalies in streptozotocin (STZ) induced type 1 diabetic rats. Male Wistar rats were fed either control or carrot powder containing diet for 3 weeks. Type 1 diabetes was induced with STZ injection (65 mg/kg body weight) in half of the rats in each group. All rats were continued on their respective diet for a further 9 weeks. Cardiac structural and functional parameters were measured using echocardiography at 8 weeks post STZ administration. In comparison to non-diabetic rats, diabetic rats showed significant increase in isovolumetric relaxation time and a significant decrease in systolic function parameter, cardiac output. Left ventricular internal dimension and left ventricular posterior wall thickness were significantly higher in diabetic animals. Blood glucose levels were significantly lower in carrot supplemented diabetic rats when compared with non-treated diabetic rats. Diabetic rats treated and untreated had elevated level of lipid peroxidation. Catalase levels were significantly elevated in the carrot powder supplemented diabetic rats when compared to the control rats. Carrot supplementation lowered blood glucose levels significantly but did not normalize it to control levels. It had no effect on cardiac abnormalities and anti-oxidant status in rats with type 1 diabetes.
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Affiliation(s)
- Xavier Lieben Louis
- Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg R3T2N2, Canada
| | - Pema Raj
- Canadian Centre for Agri-Food Research in Health and Medicine, Winnipeg R2H 2A6, Canada.,Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg R3E0J, Canada
| | - Kathleen J McClinton
- Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg R3T2N2, Canada
| | - Liping Yu
- Canadian Centre for Agri-Food Research in Health and Medicine, Winnipeg R2H 2A6, Canada.,Agriculture and Agri-Food Canada, Winnipeg R2H 2A6, Canada
| | - Miyoung Suh
- Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg R3T2N2, Canada
| | - Thomas Netticadan
- Canadian Centre for Agri-Food Research in Health and Medicine, Winnipeg R2H 2A6, Canada.,Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg R3E0J, Canada.,Agriculture and Agri-Food Canada, Winnipeg R2H 2A6, Canada
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8
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Inoue T, Sonoda N, Hiramatsu S, Kimura S, Ogawa Y, Inoguchi T. Serum Bilirubin Concentration is Associated with Left Ventricular Remodeling in Patients with Type 2 Diabetes Mellitus: A Cohort Study. Diabetes Ther 2018; 9:331-338. [PMID: 29335891 PMCID: PMC5801254 DOI: 10.1007/s13300-018-0368-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Indexed: 01/19/2023] Open
Abstract
INTRODUCTION Previous studies have shown that serum bilirubin concentration is inversely associated with the risk of cardiovascular disease. The relationship between serum bilirubin concentration and left ventricular geometry, however, has not been investigated in patients with diabetes mellitus. METHODS In this cohort study, 158 asymptomatic patients with type 2 diabetes mellitus without overt heart disease were enrolled. Left ventricular structure and function were assessed using echocardiography. Serum bilirubin concentration, glycemic control, lipid profile, and other clinical characteristics were evaluated, and their association with left ventricular geometry was determined. Patients with New York Heart Association Functional Classification greater than I, left ventricular ejection fraction less than 50%, history of coronary artery disease, severe valvulopathy, chronic atrial fibrillation, or creatinine clearance less than 30 ml/min, and those receiving insulin treatment, were excluded. RESULTS Univariate analyses showed that relative wall thickness (RWT) was significantly correlated with diastolic blood pressure (P = 0.003), HbA1c (P = 0.024), total cholesterol (P = 0.043), urinary albumin (P = 0.023), and serum bilirubin concentration (P = 0.009). There was no association between left ventricular mass index and serum bilirubin concentration. Multivariate linear regression analysis showed that log RWT was positively correlated with diastolic blood pressure (P = 0.010) and that log RWT was inversely correlated with log bilirubin (P = 0.003). In addition, the patients with bilirubin less than 0.8 mg/dl had a higher prevalence of concentric left ventricular remodeling compared with those with bilirubin 0.8 mg/dl or more. CONCLUSION Our study shows that the serum bilirubin concentration may be associated with the progression of concentric left ventricular remodeling in patients with type 2 diabetes mellitus.
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Affiliation(s)
- Tomoaki Inoue
- Department of Diabetes Mellitus and Endocrinology, Tagawa Municipal Hospital, Fukuoka, Japan.
- Department of Diabetes Mellitus and Endocrinology, Hamanomachi Hospital, Fukuoka, Japan.
| | - Noriyuki Sonoda
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinsuke Hiramatsu
- Department of Diabetes Mellitus and Endocrinology, Hamanomachi Hospital, Fukuoka, Japan
| | - Shinichiro Kimura
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihiro Ogawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Molecular and Cellular Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Toyoshi Inoguchi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Crespo MJ, Roman M, Matias J, Morales M, Torres H, Quidgley J. Synergistic Effects of Dantrolene and Nimodipine on the Phenylephrine-Induced Contraction and ACh-Induced Relaxation in Aortic Rings from Diabetic Rats. Int J Endocrinol 2018; 2018:9790303. [PMID: 29849627 PMCID: PMC5933070 DOI: 10.1155/2018/9790303] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 02/27/2018] [Indexed: 12/24/2022] Open
Abstract
Diabetics have a higher risk of developing cerebral vasospasms (CVSP) than nondiabetics. The addition of the ryanodine receptor (RyR) blocker dantrolene to standard therapies reduces vasospasms in nondiabetics. Whether diabetics with CVSP also benefit from this drug, however, is unknown. We evaluated the effects of a 30 min incubation with dantrolene (50 μM), nimodipine (50 nM), and both drugs in combination, on phenylephrine- (PHE-) induced contraction and on acetylcholine- (ACh-) induced relaxation in aortic rings from streptozotocin (STZ) diabetic rats. Age-matched, nondiabetic rats served as controls. The oxidative stress markers malondialdehyde (MDA) and 4-hydroxyalkenal (4-HAE) were also evaluated in the presence and absence of dantrolene and nimodipine. The combination of these two drugs acted synergistically to reduce the PHE-induced contraction by 80% in both diabetics and controls. In contrast, it increased the Emax value for ACh-induced relaxation (from 56.46 ± 5.14% to 96.21 ± 7.50%; n = 6, P < 0.05), and it decreased MDA + 4-HAE values in diabetic rats only. These results suggest that the combination of dantrolene and nimodipine benefits both diabetics and nondiabetics by decreasing arterial tone synergistically.
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Affiliation(s)
- Maria J. Crespo
- Department of Physiology, University of Puerto Rico-School of Medicine, San Juan, PR, USA
- Department of Anesthesiology, University of Puerto Rico-School of Medicine, San Juan, PR, USA
| | - Marie Roman
- Department of Physiology, University of Puerto Rico-School of Medicine, San Juan, PR, USA
| | - Jonathan Matias
- Department of Anesthesiology, University of Puerto Rico-School of Medicine, San Juan, PR, USA
| | - Myrna Morales
- Department of Anesthesiology, University of Puerto Rico-School of Medicine, San Juan, PR, USA
| | - Hector Torres
- Department of Anesthesiology, University of Puerto Rico-School of Medicine, San Juan, PR, USA
| | - Jose Quidgley
- Department of Physiology, University of Puerto Rico-School of Medicine, San Juan, PR, USA
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Mustafa HN, Hegazy GA, Awdan SAE, AbdelBaset M. Protective role of CoQ10 or L-carnitine on the integrity of the myocardium in doxorubicin induced toxicity. Tissue Cell 2017; 49:410-426. [DOI: 10.1016/j.tice.2017.03.007] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 03/15/2017] [Accepted: 03/31/2017] [Indexed: 01/06/2023]
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11
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Ahmed SM, Abdelrahman SA, Salama AE. Efficacy of gold nanoparticles against isoproterenol induced acute myocardial infarction in adult male albino rats. Ultrastruct Pathol 2017; 41:168-185. [PMID: 28277146 DOI: 10.1080/01913123.2017.1281367] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
This study was undertaken to investigate the role of gold nanoparticles (GNPs) of 50 nm diameter on isoproterenol (ISO) induced acute myocardial infarction in adult male albino rats. Forty five adult Wistar male albino rats were equally divided into three groups. Control (group I) was further subdivided into three subgroups. In group II, the rats received ISO subcutaneously at a dose of 100 mg/kg for three days. In group III, rats received ISO as group II and then GNPs (400 μg/kg/day) intravenously for 14 consecutive days. Echocardiography was performed. Left ventricular specimens were prepared for H&E, van Gieson staining, immunohistochemical analysis for (eNOs and Bcl-2), and Electron microscope examination. Energy dispersive X-ray microanalysis was also performed. Cardiac markers such as creatine Kinase-MB (CK-MB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and cardiac troponin T (cTnT) were measured. Group II revealed cardiomyocytes with deeply stained acidophilic cytoplasm, small dark nuclei, intracellular vacuolations, wide intercellular spaces, and extravasated red blood cells. Increased collagen fibers were observed. Electron microscope examination showed cardiomyocyte with small and irregular outlined nuclei, mitochondria with irregular cristae and others with ruptured mitochondrial membrane, abnormal alignment of myofibrils, dilated cisternae of smooth endoplasmic reticulum, and disorganized intercalated discs. Group III showed that most cardiomyocytes preserved the normal architecture. Increased expression of eNOs immunoreaction and decreased Bcl-2 immunoreaction were detected in group II as compared to the control and GNP-treated groups. These findings suggested that GNPs of 50 nm diameter improved myocardial injury after ISO-induced myocardial infarction in rats. ABBREVIATIONS Myocardial infarction (MI), Isoproterenol (ISO), Nitric oxide (NO), Neuronal NOS (nNOs), Endothelial NOs (eNOs), Gold nanoparticle (GNPs), Diamiobenzidine (DAB), Serum Creatine Kinase-MB (CK-MB), Alanine aminotransferase (ALT), Cardiac troponin T (cTnT), Electrochemiluminiscence (ECLIA), Cardiomyocytes (CMC), Peroxisomal proliferator activated receptor (PPARs), Reactive oxygen species (ROS).
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Affiliation(s)
- Samah M Ahmed
- a Histology and Cell Biology Department, Faculty of Human Medicine , Zagazig University , Zagazig , Egypt
| | - Shaimaa Ali Abdelrahman
- a Histology and Cell Biology Department, Faculty of Human Medicine , Zagazig University , Zagazig , Egypt
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12
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Amoni M, Kelly-Laubscher R, Blackhurst D, Gwanyanya A. Beneficial Effects of Magnesium Treatment on Heart Rate Variability and Cardiac Ventricular Function in Diabetic Rats. J Cardiovasc Pharmacol Ther 2016; 22:169-178. [PMID: 27276916 DOI: 10.1177/1074248416653831] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND Diabetes mellitus induces life-threatening cardiovascular complications such as cardiac autonomic neuropathy and ventricular dysfunction and is associated with hypomagnesemia. In this study, we investigated the short-term effects of magnesium (Mg2+) treatment on streptozotocin (STZ)-induced diabetic cardiac complications. METHODS Adult Wistar rats were treated once with STZ (50 mg/kg, intraperitoneally [ip]) or vehicle (citrate) and then daily for 7 days with MgSO4 (270 mg/kg, ip) or saline. On the eighth day, in vivo tail-pulse plethysmography was recorded for heart rate variability (HRV) analysis, and ex vivo Langendorff-based left ventricular (LV) pressure-volume parameters were measured using an intraventricular balloon. Measurements of plasma lipid and Mg2+ levels as well as blood glucose and cardiac tissue Mg2+ levels were also performed. RESULTS Treatment with Mg2+ prevented diabetes-induced alterations in the standard deviation of the averages of normal-to-normal (NN) intervals (SDANN), root mean square differences of successive NN intervals (RMSSD), heart rate, and low-frequency (LF) power-high-frequency (HF) power ratio. In addition, Mg2+ restored orthostatic stress-induced changes in SDANN, RMSSD, and LF-HF ratio in diabetic rats. In isolated hearts, Mg2+ reversed the diabetes-induced decrease in LV end-diastolic elastance and the right shift of end-diastolic equilibrium volume intercept, without altering LV-developed pressure or end-systolic elastance. However, Mg2+ did not prevent the elevation in blood glucose, total cholesterol, and triglycerides or the decrease in high-density lipoprotein cholesterol in diabetes. Plasma- or cardiac tissue Mg2+ was not different among the treatment groups. CONCLUSION These results suggest that Mg2+ treatment may attenuate diabetes-induced reduction in HRV and improve LV diastolic distensibility, without preventing hyperglycemia and dyslipidemia. Thus, Mg2+ may have a modulatory role in the early stages of diabetic cardiovascular complications.
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Affiliation(s)
- Matthew Amoni
- 1 Department of Human Biology, University of Cape Town, Cape Town, South Africa
| | - Roisin Kelly-Laubscher
- 2 Department of Biological Sciences, University of Cape Town, Cape Town, South Africa.,3 Centre for Higher Education Development, University of Cape Town, Cape Town, South Africa
| | - Dee Blackhurst
- 4 Department of Pathology, University of Cape Town, Cape Town, South Africa
| | - Asfree Gwanyanya
- 1 Department of Human Biology, University of Cape Town, Cape Town, South Africa
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13
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Crespo MJ, Quidgley J. Simvastatin, atorvastatin, and pravastatin equally improve the hemodynamic status of diabetic rats. World J Diabetes 2015; 6:1168-78. [PMID: 26322162 PMCID: PMC4549667 DOI: 10.4239/wjd.v6.i10.1168] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2015] [Revised: 07/28/2015] [Accepted: 08/16/2015] [Indexed: 02/05/2023] Open
Abstract
AIM To investigate if the effect of statins improving cardiovascular (CV) status of diabetics is drug-specific or class-dependent, and the underlying mechanisms involved. METHODS We compared the results of daily administration over a four-week period of a low dose (10 mg/kg per day) of atorvastatin (AV), simvastatin (SV), and pravastatin (PV) on cardiac performance in diabetic rats. Echocardiographic variables were tested, as well as systolic blood pressure (SBP), acetylcholine (ACh)-induced relaxation, plasma cholesterol levels, and perivascular fibrosis. Malondialdehyde (MDA) and 4-hydroxyalkenal (4-HAE), and endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) protein levels were also measured in cardiac and aortic homogenates. RESULTS In untreated diabetic rats, cholesterol levels were higher than in control rats (CT; n = 8, P < 0.05), and the low dose of statins used did not modify these levels. In diabetic rats, SBP was higher than in CT, and was significantly reduced by all three statins (n = 10, P < 0.05). Echocardiographic parameters (EF, SV, and COI) were all lower in untreated diabetic rats than in CT (n = 10, P < 0.05). These CV parameters were equally improved by all three statins. The maximal relaxation (EMax) induced by ACh in aortic ring from diabetic rats was also improved. Moreover, this relaxation was abolished by 1 mmol/L NG-nitro-L-arginine methyl ester, suggesting the involvement of a NO-dependent mechanism. CONCLUSION AV, SV, and PV are equally effective in improving CV performance in diabetic rats. All tree statins decreased media thickness, perivascular fibrosis, and both MDA and 4-HAE in the aortas of diabetic rats, without affecting eNOS and iNOS protein levels. The observed hemodynamic benefits are cholesterol-independent. These benefits appear to be secondary to the improved endothelial function, and to the reduced vascular tone and remodeling that result from decreased oxidative stress.
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14
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Smirnova EA, Michunskaya AB, Terekhina OL, Kobozeva LP, Kruglov SV, Belkina LM, Pozdnyakov OM. Effect of Nitric Oxide Synthesis Blockade on the Morphology of Langerhans Islets in August and Wistar Rats with Acute Alloxan Diabetes. Bull Exp Biol Med 2015; 159:273-7. [PMID: 26085363 DOI: 10.1007/s10517-015-2940-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Indexed: 10/23/2022]
Abstract
Alloxan diabetes was modeled in August rats with high activity of the NO system and in Wistar rats, and the effects of NO system blockade (by a course treatment with L-NNA) on Langerhans islet β cells were studied in 15 days. The toxic effects of diabetes on the rat β cells and islets were similar: the content of active β cells in the islets decreased to 15-20%, the number of islets to 24-29% of control. A course of L-NNA reduced the β cell and islet death, in August cells greater than in Wistar: the number of islets in August rats was restored to 81%, in Wistar rats to 60% of initial level; the activity of β cells remained at the control level in the former and 2-fold lower than in the control in the latter. It seems that a less pronounced protective effect of L-NNA in Wistar rats was explained by excessive reduction of NO level essential for β cell regeneration.
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Affiliation(s)
- E A Smirnova
- Research Institute of Pathology and Pathophysiology, Russian Academy of Medical Sciences, Moscow, Russia
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15
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Semaming Y, Kumfu S, Pannangpetch P, Chattipakorn SC, Chattipakorn N. Protocatechuic acid exerts a cardioprotective effect in type 1 diabetic rats. J Endocrinol 2014; 223:13-23. [PMID: 25074852 DOI: 10.1530/joe-14-0273] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Oxidative stress has been shown to play an important role in the pathogenesis of diabetes-induced cardiac dysfunction. Protocatechuic acid (PCA) is a phenolic compound, a main metabolite of anthocyanin, which has been reported to display various pharmacological properties. We proposed the hypothesis that PCA exerts cardioprotection in type 1 diabetic (T1DM) rats. T1DM was induced in male Sprague-Dawley rats by a single i.p. injection of 50 mg/kg streptozotocin (STZ) and groups of these animals received the following treatments for 12 weeks: i) oral administration of vehicle, ii) oral administration of PCA at a dose of 50 mg/kg per day, iii) oral administration of PCA at a dose of 100 mg/kg per day, iv) s.c. injection of insulin at a dose of 4 U/kg per day, and v) a combination of PCA, 100 mg/kg per day and insulin, 4 U/kg per day. Metabolic parameters, results from echocardiography, and heart rate variability were monitored every 4 weeks, and the HbA1c, cardiac malondialdehyde (MDA), cardiac mitochondrial function, and cardiac BAX/BCL2 expression were evaluated at the end of treatment. PCA, insulin, and combined drug treatments significantly improved metabolic parameters and cardiac function as shown by increased percentage fractional shortening and percentage left ventricular ejection fraction and decreased low-frequency:high-frequency ratio in T1DM rats. Moreover, all treatments significantly decreased plasma HbA1c and cardiac MDA levels, improved cardiac mitochondrial function, and increased BCL2 expression. Our results demonstrated for the first time, to our knowledge, the efficacy of PCA in improving cardiac function and cardiac autonomic balance, preventing cardiac mitochondrial dysfunction, and increasing anti-apoptotic protein in STZ-induced T1DM rats. Thus, PCA possesses a potential cardioprotective effect and could restore cardiac function when combined with insulin treatment. These findings indicated that supplementation with PCA might be helpful for the prevention and alleviation of cardiovascular complications in T1DM.
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MESH Headings
- Administration, Oral
- Animals
- Anticarcinogenic Agents/administration & dosage
- Anticarcinogenic Agents/pharmacology
- Blotting, Western
- Cardiotonic Agents/administration & dosage
- Cardiotonic Agents/pharmacology
- Diabetes Mellitus, Experimental/blood
- Diabetes Mellitus, Experimental/drug therapy
- Diabetes Mellitus, Experimental/physiopathology
- Diabetes Mellitus, Type 1/blood
- Diabetes Mellitus, Type 1/drug therapy
- Diabetes Mellitus, Type 1/physiopathology
- Drug Therapy, Combination
- Echocardiography
- Glycated Hemoglobin/metabolism
- Heart/drug effects
- Heart/physiopathology
- Hydroxybenzoates/administration & dosage
- Hydroxybenzoates/pharmacology
- Hypoglycemic Agents/administration & dosage
- Hypoglycemic Agents/therapeutic use
- Insulin/administration & dosage
- Insulin/blood
- Insulin/therapeutic use
- Male
- Malondialdehyde/blood
- Malondialdehyde/metabolism
- Mitochondria, Heart/drug effects
- Mitochondria, Heart/metabolism
- Mitochondria, Heart/physiology
- Myocardium/metabolism
- Proto-Oncogene Proteins c-bcl-2/metabolism
- Rats
- Rats, Sprague-Dawley
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Affiliation(s)
- Yoswaris Semaming
- Cardiac Electrophysiology Research and Training CenterFaculty of Medicine, Chiang Mai University, Chiang Mai 50200, ThailandDepartment of PharmacologyFaculty of Medicine, Khon Kaen University, Khon Kaen 40002, ThailandCardiac Electrophysiology UnitDepartment of Physiology, Faculty of MedicineDepartment of Oral Biology and Diagnostic SciencesFaculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand Cardiac Electrophysiology Research and Training CenterFaculty of Medicine, Chiang Mai University, Chiang Mai 50200, ThailandDepartment of PharmacologyFaculty of Medicine, Khon Kaen University, Khon Kaen 40002, ThailandCardiac Electrophysiology UnitDepartment of Physiology, Faculty of MedicineDepartment of Oral Biology and Diagnostic SciencesFaculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Sirinart Kumfu
- Cardiac Electrophysiology Research and Training CenterFaculty of Medicine, Chiang Mai University, Chiang Mai 50200, ThailandDepartment of PharmacologyFaculty of Medicine, Khon Kaen University, Khon Kaen 40002, ThailandCardiac Electrophysiology UnitDepartment of Physiology, Faculty of MedicineDepartment of Oral Biology and Diagnostic SciencesFaculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand Cardiac Electrophysiology Research and Training CenterFaculty of Medicine, Chiang Mai University, Chiang Mai 50200, ThailandDepartment of PharmacologyFaculty of Medicine, Khon Kaen University, Khon Kaen 40002, ThailandCardiac Electrophysiology UnitDepartment of Physiology, Faculty of MedicineDepartment of Oral Biology and Diagnostic SciencesFaculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Patchareewan Pannangpetch
- Cardiac Electrophysiology Research and Training CenterFaculty of Medicine, Chiang Mai University, Chiang Mai 50200, ThailandDepartment of PharmacologyFaculty of Medicine, Khon Kaen University, Khon Kaen 40002, ThailandCardiac Electrophysiology UnitDepartment of Physiology, Faculty of MedicineDepartment of Oral Biology and Diagnostic SciencesFaculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand Cardiac Electrophysiology Research and Training CenterFaculty of Medicine, Chiang Mai University, Chiang Mai 50200, ThailandDepartment of PharmacologyFaculty of Medicine, Khon Kaen University, Khon Kaen 40002, ThailandCardiac Electrophysiology UnitDepartment of Physiology, Faculty of MedicineDepartment of Oral Biology and Diagnostic SciencesFaculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Siriporn C Chattipakorn
- Cardiac Electrophysiology Research and Training CenterFaculty of Medicine, Chiang Mai University, Chiang Mai 50200, ThailandDepartment of PharmacologyFaculty of Medicine, Khon Kaen University, Khon Kaen 40002, ThailandCardiac Electrophysiology UnitDepartment of Physiology, Faculty of MedicineDepartment of Oral Biology and Diagnostic SciencesFaculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand Cardiac Electrophysiology Research and Training CenterFaculty of Medicine, Chiang Mai University, Chiang Mai 50200, ThailandDepartment of PharmacologyFaculty of Medicine, Khon Kaen University, Khon Kaen 40002, ThailandCardiac Electrophysiology UnitDepartment of Physiology, Faculty of MedicineDepartment of Oral Biology and Diagnostic SciencesFaculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Nipon Chattipakorn
- Cardiac Electrophysiology Research and Training CenterFaculty of Medicine, Chiang Mai University, Chiang Mai 50200, ThailandDepartment of PharmacologyFaculty of Medicine, Khon Kaen University, Khon Kaen 40002, ThailandCardiac Electrophysiology UnitDepartment of Physiology, Faculty of MedicineDepartment of Oral Biology and Diagnostic SciencesFaculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand Cardiac Electrophysiology Research and Training CenterFaculty of Medicine, Chiang Mai University, Chiang Mai 50200, ThailandDepartment of PharmacologyFaculty of Medicine, Khon Kaen University, Khon Kaen 40002, ThailandCardiac Electrophysiology UnitDepartment of Physiology, Faculty of MedicineDepartment of Oral Biology and Diagnostic SciencesFaculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand
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16
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Khanna S, Singh GB, Khullar M. Nitric oxide synthases and diabetic cardiomyopathy. Nitric Oxide 2014; 43:29-34. [PMID: 25153033 DOI: 10.1016/j.niox.2014.08.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Revised: 07/22/2014] [Accepted: 08/14/2014] [Indexed: 01/06/2023]
Abstract
Cardiovascular complications associated with diabetes significantly contribute to high mortality and morbidity worldwide. The pathophysiology of diabetic cardiomyopathy (DCM), although extensively researched upon, is partially understood. Impairment in various signaling pathways including nitric oxide (NO) signaling has been implicated in the pathogenesis of diabetes induced myocardial damage. Nitric oxide synthases (NOS), the enzymes responsible for NO generation, play an important role in various physiological processes. Altered expression and activity of NOS have been implicated in cardiovascular diseases, however, the role of NOS and their regulation in the pathogenesis of DCM remain poorly understood. In the present review, we focus on the role of myocardial NOS in the development of DCM. Since epigenetic modifications play an important role in regulation of gene expression, this review also describes the epigenetic regulation of NOS.
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Affiliation(s)
- Sanskriti Khanna
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Gurinder Bir Singh
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Madhu Khullar
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
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17
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Maeda Y, Inoguchi T, Takei R, Hendarto H, Ide M, Inoue T, Kobayashi K, Urata H, Nishiyama A, Takayanagi R. Chymase inhibition prevents myocardial fibrosis through the attenuation of NOX4-associated oxidative stress in diabetic hamsters. J Diabetes Investig 2014; 3:354-61. [PMID: 24843590 PMCID: PMC4019255 DOI: 10.1111/j.2040-1124.2012.00202.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
UNLABELLED Aims/Introduction: Diabetic cardiomyopathy entails the cardiac injury induced by diabetes, independent of vascular disease or hypertension. Despite numerous experimental studies and clinical trials, the pathogenesis of diabetic cardiomyopathy remains elusive. Here, we report that chymase, an immediate angiotensin II (AngII)-forming enzyme in humans and hamsters, and NOX4-induced oxidative stress have pathogenic roles in myocardial fibrosis in diabetic hamsters. MATERIALS AND METHODS Expression of chymase was evaluated in the hearts of streptozotocin (STZ)-induced diabetic hamsters. The impact of chymase-specific inhibitors, TEI-E00548 and TEI-F00806, on myocardial fibrosis, and increased levels of intracardiac AngII, accumulation of 8-hydroxy-2'-deoxyguanosine (an oxidative stress marker in urine and heart tissue) and expression of heart NOX4 in diabetic hamsters were investigated. RESULTS Myocardial chymase expression was markedly upregulated in STZ hamsters in a glucose-dependent manner. A total of 8 weeks after STZ administration, the diabetic hamsters showed enhanced oxidative stress and NOX4 expression in the heart, in parallel with increased myocardial AngII production. Oral administration of chymase-specific inhibitors, TEI-F00806 and TEI-E00548, normalized heart AngII levels, and completely reversed NOX4-induced oxidative stress and myocardial fibrosis in STZ-induced diabetic hamsters, although they did not affect the activity of the systemic renin-angiotensin system or systolic blood pressure. CONCLUSIONS Chymase inhibition might prevent oxidative stress and diabetic cardiomyopathy at an early stage by reducing local AngII production. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2012.00202.x, 2012).
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Affiliation(s)
- Yasutaka Maeda
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences
| | - Toyoshi Inoguchi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences ; Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka
| | - Ryoko Takei
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences
| | - Hari Hendarto
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences
| | - Makoto Ide
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences
| | - Tomoaki Inoue
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences
| | - Kunihisa Kobayashi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences
| | - Hidenori Urata
- Department of Internal Medicine, Fukuoka University, Chikushi Hospital, Chikushino
| | - Akira Nishiyama
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Ryoichi Takayanagi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences
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18
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Quidgley J, Cruz N, Crespo MJ. Atorvastatin improves systolic function, but does not prevent the development of dilated cardiomyopathy in streptozotocin-induced diabetic rats. Ther Adv Cardiovasc Dis 2014; 8:133-144. [PMID: 24759610 DOI: 10.1177/1753944714531065] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Therapy with HMG-CoA reductase inhibitors (statins) has been associated with a significant reduction in the number of major cardiovascular (CV) events in diabetic patients. The mechanisms by which these drugs improve cardiac status remain unclear. We assessed the effects of atorvastatin (10 mg/kg/day) on CV function in streptozotocin (STZ)-induced diabetic rats. METHODS Age-matched, nondiabetic rats were used as controls. Echocardiographic parameters, systolic blood pressure (SBP), endothelial-dependent relaxation, cardiac and vascular oxidative stress, perivascular fibrosis, and cholesterol levels were evaluated after a 4-week atorvastatin treatment period. RESULTS In diabetic rats, SBP was higher than in controls. Atorvastatin decreased SBP in diabetic rats by 14% (n = 10, p < 0.05), and significantly increased stroke volume, ejection fraction, and cardiac output index. Whereas atorvastatin reduced left ventricular end systolic volume (LVESV) by 50% (p < 0.05), it failed to reduce left ventricular end diastolic volume (LVEDV). Total cholesterol was higher in diabetic rats than in controls and atorvastatin was ineffective in reducing cholesterol levels. The statin, however, decreased perivascular fibrosis and media thickness, and the markers of oxidative stress malondialdehyde (MDA) and 4-hidroxyalkenals (4-HAE) in aortic homogenates from diabetic rats. In addition, atorvastatin improved endothelial function by increasing the E MAX value of the acetylcholine-induced relaxation from 53.7 ± 4.1% in untreated diabetic to 82.1 ± 7.0% in treated diabetic rats (n = 10, p < 0.05). L-NAME fully abolished this improvement, suggesting that the increased vascular relaxation with atorvastatin is NO-dependent. CONCLUSIONS Whereas atorvastatin does not reverse ventricular dilatation, it does have a positive hemodynamic effect on the CV system of diabetic rats. This hemodynamic benefit is independent of cholesterol levels, and is observed concomitantly with reduced oxidative stress, vascular remodeling, and improved endothelial function. Together, these results suggest that atorvastatin decreases the workload on the heart and improves systolic performance in type 1 diabetic rats by reducing oxidative stress, vascular tone, and systemic vascular resistance.
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Affiliation(s)
- Jose Quidgley
- Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico
| | - Nildris Cruz
- Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico
| | - Maria J Crespo
- Departments of Physiology and Anesthesiology, School of Medicine, University of Puerto Rico, PO Box 365067, San Juan, PR 00936-5067, Puerto Rico
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19
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Mosquera L, Colón JM, Santiago JM, Torrado AI, Meléndez M, Segarra AC, Rodríguez-Orengo JF, Miranda JD. Tamoxifen and estradiol improved locomotor function and increased spared tissue in rats after spinal cord injury: their antioxidant effect and role of estrogen receptor alpha. Brain Res 2014; 1561:11-22. [PMID: 24637260 DOI: 10.1016/j.brainres.2014.03.002] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Revised: 02/20/2014] [Accepted: 03/05/2014] [Indexed: 12/17/2022]
Abstract
17β-Estradiol is a multi-active steroid that imparts neuroprotection via diverse mechanisms of action. However, its role as a neuroprotective agent after spinal cord injury (SCI), or the involvement of the estrogen receptor-alpha (ER-α) in locomotor recovery, is still a subject of much debate. In this study, we evaluated the effects of estradiol and of Tamoxifen (an estrogen receptor mixed agonist/antagonist) on locomotor recovery following SCI. To control estradiol cyclical variability, ovariectomized female rats received empty or estradiol filled implants, prior to a moderate contusion to the spinal cord. Estradiol improved locomotor function at 7, 14, 21, and 28 days post injury (DPI), when compared to control groups (measured with the BBB open field test). This effect was ER-α mediated, because functional recovery was blocked with an ER-α antagonist. We also observed that ER-α was up-regulated after SCI. Long-term treatment (28 DPI) with estradiol and Tamoxifen reduced the extent of the lesion cavity, an effect also mediated by ER-α. The antioxidant effects of estradiol were seen acutely at 2 DPI but not at 28 DPI, and this acute effect was not receptor mediated. Rats treated with Tamoxifen recovered some locomotor activity at 21 and 28 DPI, which could be related to the antioxidant protection seen at these time points. These results show that estradiol improves functional outcome, and these protective effects are mediated by the ER-α dependent and independent-mechanisms. Tamoxifen׳s effects during late stages of SCI support the use of this drug as a long-term alternative treatment for this condition.
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Affiliation(s)
- Laurivette Mosquera
- Department of Physiology, University of Puerto Rico-School of Medicine, San Juan, PR 00936, USA
| | - Jennifer M Colón
- Department of Physiology, University of Puerto Rico-School of Medicine, San Juan, PR 00936, USA
| | - José M Santiago
- University of Puerto Rico Carolina Campus, Department of Natural Sciences, Carolina, PR 00984, USA
| | - Aranza I Torrado
- Department of Physiology, University of Puerto Rico-School of Medicine, San Juan, PR 00936, USA
| | | | - Annabell C Segarra
- Department of Physiology, University of Puerto Rico-School of Medicine, San Juan, PR 00936, USA
| | - José F Rodríguez-Orengo
- Department of Biochemistry, University of Puerto Rico-School of Medicine, San Juan, PR 00936, USA
| | - Jorge D Miranda
- Department of Physiology, University of Puerto Rico-School of Medicine, San Juan, PR 00936, USA.
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Abstract
We studied the effects of N(w)-nitro-L-arginine (L-NNA), a nonselective inhibitor of NO synthases, on the severity of type 1 diabetes mellitus induced by subcutaneous injection of 130 mg/kg alloxan in August rats with high activity of NO system and in Wistar rats. Five days after alloxan injection, hyperglycemia levels after overnight fasting in August and Wistar rats were 27.1±3.7 and 22.0±1.1 mmol/liter, respectively (p<0.03). The mortality over 15 days after alloxan injection in August rats was higher than in Wistar rats (36 and 26%, respectively). L-NNA normalized glucose levels in diabetics of both groups. It completely prevented mortality in August and reduced it to 13% in Wistar rats. Body weight loss and polydipsia after L-NNA injection were also less pronounced in August rats. Plasma nitrite/nitrate concentrations in August rats were 32% higher than in Wistar rats, both in intact and diabetic rats. These data attest to an important role of NO in the pathogenesis of alloxan diabetes.
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21
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Crespo MJ, Cruz N, Quidgley J, Torres H, Hernandez C, Casiano H, Rivera K. Daily Administration of Atorvastatin and Simvastatin for One Week Improves Cardiac Function in Type 1 Diabetic Rats. Pharmacology 2014; 93:84-91. [DOI: 10.1159/000358256] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Accepted: 12/24/2013] [Indexed: 12/15/2022]
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22
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Rashid K, Sinha K, Sil PC. An update on oxidative stress-mediated organ pathophysiology. Food Chem Toxicol 2013; 62:584-600. [PMID: 24084033 DOI: 10.1016/j.fct.2013.09.026] [Citation(s) in RCA: 94] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2013] [Revised: 08/29/2013] [Accepted: 09/19/2013] [Indexed: 12/29/2022]
Abstract
Exposure to environmental pollutants and drugs can result in pathophysiological situations in the body. Research in this area is essential as the knowledge on cellular survival and death would help in designing effective therapeutic strategies that are needed for the maintenance of the normal physiological functions of the body. In this regard, naturally occurring bio-molecules can be considered as potential therapeutic targets as they are normally available in commonly consumed foodstuffs and are thought to have minimum side effects. This review article describes the detailed mechanisms of oxidative stress-mediated organ pathophysiology and the ultimate fate of the cells either to survive or to undergo necrotic or apoptotic death. The mechanisms underlying the beneficial role of a number of naturally occurring bioactive molecules in oxidative stress-mediated organ pathophysiology have also been included in the review. The review provides useful information about the recent progress in understanding the mechanism(s) of various types of organ pathophysiology, the complex cross-talk between these pathways, as well as their modulation in stressed conditions. Additionally, it suggests possible therapeutic applications of a number of naturally occurring bioactive molecules in conditions involving oxidative stress.
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Affiliation(s)
- Kahkashan Rashid
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Calcutta 700054, West Bengal, India
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Shida T, Nozawa T, Sobajima M, Ihori H, Matsuki A, Inoue H. Fluvastatin-induced reduction of oxidative stress ameliorates diabetic cardiomyopathy in association with improving coronary microvasculature. Heart Vessels 2013; 29:532-41. [PMID: 23979266 DOI: 10.1007/s00380-013-0402-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Accepted: 08/09/2013] [Indexed: 12/15/2022]
Abstract
Diabetic cardiomyopathy is associated with increased oxidative stress and vascular endothelial dysfunction, which lead to coronary microangiopathy. We tested whether statin-induced redox imbalance improvements could ameliorate diabetic cardiomyopathy and improve coronary microvasculature in streptozotocin-induced diabetes mellitus (DM). Fluvastatin (10 mg/kg/day) or vehicle was orally administered for 12 weeks to rats with or without DM. Myocardial oxidative stress was assessed by NADPH (nicotinamide adenine dinucleotide phosphate) oxidase subunit p22(phox) and gp91(phox) mRNA expression, and myocardial 8-iso-prostaglandin F(2α) (PGF(2α)) levels. Myocardial vascular densities were assessed using anti-CD31 and anti-α-smooth muscle actin (SMA) antibodies. Fluvastatin did not affect blood pressure or plasma cholesterol, but attenuated increased left ventricular (LV) minimum pressure and ameliorated LV systolic dysfunction in DM rats in comparison with vehicle (LV dP/dt, 8.9 ± 1.8 vs 5.4 ± 1.0 × 10(3) mmHg/s, P < 0.05). Myocardial oxidative stress increased in DM, but fluvastatin significantly reduced p22(phox) and gp91(phox) mRNA expression and myocardial PGF(2α) levels. Fluvastatin enhanced myocardial endothelial nitric oxide synthase (eNOS) protein levels and increased eNOS, vascular endothelial growth factor, and hypoxia-inducible factor-1α mRNA expression. CD31-positive cell densities were lower in DM rats than in non-DM rats (28.4 ± 13.2 vs 48.6 ± 4.3/field, P < 0.05) and fluvastatin restored the number (57.8 ± 18.3/field), although there were no significant differences in SMA-positive cell densities between groups. Fluvastatin did not affect cardiac function, oxidative stress, or vessel densities in non-DM rats. These results suggest that beneficial effects of fluvastatin on diabetic cardiomyopathy might result, at least in part, from improving coronary microvasculature through reduction in myocardial oxidative stress and upregulation of angiogenic factor.
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Affiliation(s)
- Takuya Shida
- Second Department of Internal Medicine, Graduate School of Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
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Inoue T, Kobayashi K, Inoguchi T, Sonoda N, Maeda Y, Hirata E, Fujimura Y, Miura D, Hirano KI, Takayanagi R. Downregulation of adipose triglyceride lipase in the heart aggravates diabetic cardiomyopathy in db/db mice. Biochem Biophys Res Commun 2013; 438:224-9. [DOI: 10.1016/j.bbrc.2013.07.063] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Accepted: 07/16/2013] [Indexed: 10/26/2022]
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Ghosh J, Sil PC. Arjunolic acid: a new multifunctional therapeutic promise of alternative medicine. Biochimie 2013; 95:1098-1109. [PMID: 23402784 DOI: 10.1016/j.biochi.2013.01.016] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2012] [Accepted: 01/22/2013] [Indexed: 02/05/2023]
Abstract
IMPORTANCE OF THE FIELD In recent years, a number of studies describing the effective therapeutic strategies of medicinal plants and their active constituents in traditional medicine have been reported. Indeed, tremendous demand for the development and implementation of these plant derived biomolecules in complementary and alternative medicine is increasing and appear to be promising candidates for pharmaceutical industrial research. These new molecules, especially those from natural resources, are considered as potential therapeutic targets, because they are derived from commonly consumed foodstuff and are considered to be safe for humans. AREAS COVERED IN THIS REVIEW This review highlights the beneficial role of arjunolic acid, a naturally occurring chiral triterpenoid saponin, in various organ pathophysiology and the underlying mechanism of its protective action. Studies on the biochemistry and pharmacology suggest the potential use of arjunolic acid as a novel promising therapeutic strategy. WHAT THE READERS WILL GAIN The multifunctional therapeutic application of arjunolic acid has already been documented by its various biological functions including antioxidant, anti-fungal, anti-bacterial, anticholinesterase, antitumor, antiasthmatic, wound healing and insect growth inhibitor activities. The scientific basis behind its therapeutic application as a cardioprotective agent in traditional medicine is justified by its ability to prevent myocardial necrosis and apoptosis, platelet aggregation, coagulation and lowering of blood pressure, heart rate, as well as cholesterol levels. Its antioxidant property coupled with metal chelating property (by its two hydroxyl groups) protects different organs from metal and drug-induced organ pathophysiology. Arjunolic acid also plays a beneficial role in the pathogenesis of diabetes and its associated complications. The mechanism of cytoprotection of arjunolic acid, at least in part, results from the detoxification of reactive oxygen species (ROS) produced in the respective pathophysiology. In addition to its other biological functions, it also possesses vibrant insecticidal properties and it has the potential to be used as a structural molecular framework for the design of molecular receptors in the general area of supramolecular chemistry and nanochemistry. Esters of arjunolic acid function as organogelators which has wide application in designing thermochromic switches and sensor devices. Arjunolic acid derived crown ether is an attractive candidate for the design of molecular receptors, biomimetics and supramolecular systems capable of performing some biological functions. HOME MESSAGE This review would provide useful information about the recent progress of natural product research in the domain of clinical science. This review also aims to untie the multifunctional therapeutic application of arjunolic acid, a nanometer-long naturally occurring chiral triterpenoid biomolecule.
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Affiliation(s)
- Jyotirmoy Ghosh
- Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104, USA
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Manna P, Sil PC. Arjunolic acid: beneficial role in type 1 diabetes and its associated organ pathophysiology. Free Radic Res 2012; 46:815-830. [PMID: 22486656 DOI: 10.3109/10715762.2012.683431] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
In this review article, we describe the most recent development of the beneficial effect of arjunolic acid (AA) in reducing type 1 diabetic pathophysiology. Diabetic mellitus is a serious and growing health problem worldwide. Increasing evidence suggest that oxidative stress plays a pivotal role in the pathogenesis of diabetes and its associated complications. Use of antioxidant supplements as a complimentary therapeutic approach in diabetes has, therefore, been seriously considered worldwide. AA, a natural pentacyclic triterpenoid saponin, is well known for various biological functions including antioxidant activity. It could prevent the increased production of ROS, RNS, AGEs, and the 8OHdG/2dG ratio and increase the intracellular antioxidant defence system. Signal transduction studies showed that AA could prevent hyperglycaemia induced activation of MAPKs, PKC, NF-κB signalling cascades and apoptotic cell death. Combining, AA supplements could be regarded as beneficial therapeutics in the treatment of diabetes and its associated complications.
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Affiliation(s)
- Prasenjit Manna
- Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, LA, USA
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Manna P, Sil PC. Impaired redox signaling and mitochondrial uncoupling contributes vascular inflammation and cardiac dysfunction in type 1 diabetes: Protective role of arjunolic acid. Biochimie 2012; 94:786-797. [PMID: 22155371 DOI: 10.1016/j.biochi.2011.11.010] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2011] [Accepted: 11/24/2011] [Indexed: 01/26/2023]
Abstract
Vascular inflammation and cardiac dysfunction are the leading causes of mortality and morbidity among the diabetic patients. Type 1 diabetic mellitus (T1DM) is associated with increased cardiovascular complications at an early stage of the disease. The purpose of the present study was to explore whether arjunolic acid (AA) plays any protective role against cardiovascular complications in T1DM and if so, what molecular pathways it utilizes for the mechanism of its protective action. Streptozotocin (STZ) was used to induce T1DM in experimental rats. Alteration in plasma lipid profile and release of membrane bound enzymes like LDH (lactate dehydrogenase) and CK (creatine kinase) established the association of hyperlipidemia and cell membrane disintegration with hyperglycemia. Hyperglycemia altered the levels of oxidative stress related biomarkers, decreased the intracellular NAD and ATP concentrations. Hyperglycemia-induced enhanced levels of VEGF, ICAM-1, MCP-1 and IL-6 in the plasma of STZ treated animals indicate vascular inflammation in T1DM. Histological studies and FACS analysis revealed that hyperglycemia caused cell death mostly via the apoptotic pathway. Investigating molecular mechanism, we observed NF-κB and MAPKs (p38 and ERK1/2) activations, mitochondrial membrane depolarization, cytochrome C release, caspase 3 activation and PARP cleavage in apoptotic cell death in the diabetic cardiac tissue. Treatment with AA (20 mg/kg body weight) reduced hyperglycemia, membrane disintegration, oxidative stress, vascular inflammation and prevented the activation of oxidative stress induced signaling cascades leading to cell death. Results suggest that AA possesses the potential to be a beneficial therapeutic agent in diabetes and its associated cardiac complications.
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Affiliation(s)
- Prasenjit Manna
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700054, West Bengal, India
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Histological and immunohistochemical study on the possible cardioprotective role of acetylcysteine in oral formalin myocardial toxicity in adult albino rats. ACTA ACUST UNITED AC 2011. [DOI: 10.1097/01.ehx.0000407660.20814.6d] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Altieri PI, Figueroa Y, Banchs HL, Hernández-Gil de Lamadrid J, Escobales N, Crespo MJ. Metabolic syndrome in an Hispanic population–cardiovascular complications. QSCIENCE CONNECT 2011. [DOI: 10.5339/connect.2011.5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Abstract
The metabolic syndrome (MetS) is presently one of the main medical problems in developing countries. This syndrome was studied in Puerto Rico at the Cardiovascular Center of Puerto Rico and the Caribbean with emphasis on understanding the cardiovascular complications.
The medical records of patients admitted between 1999 to 2005 were evaluated for three or more MetS diagnostic criteria.
One hundred and seventy-three patients met the consensus criteria of metabolic syndrome (MetS). The mean age of those diagnosed with MetS was 60 years of age. Fifty-seven percent were males and 42 percent females. The mean body mass was 30 kg/m. The ejection fraction was found to be subnormal ( 49±8%) and the end systolic dimension of the left atrium was increased ( 45±10 mm) in comparison to a group of diabetic patients without MetS used for comparison. The incidence of atrial fibrillation was found to be 16% higher in the MetS group than in the comparison group.
The number of cases of metabolic syndrome recorded within the Hispanic population of Puerto Rico showed a higher incidence of atrial fibrillation without ventricular tachycardia. This is thought to be as a result of the abnormal left ventricular and atrial function.
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Affiliation(s)
- Pablo I. Altieri
- All authors: Departments of Medicine and Physiology, University of Puerto Rico School
of Medicine and the Cardiovascular Center of Puerto Rico and the Caribbean
| | - Yolanda Figueroa
- All authors: Departments of Medicine and Physiology, University of Puerto Rico School
of Medicine and the Cardiovascular Center of Puerto Rico and the Caribbean
| | - Héctor L. Banchs
- All authors: Departments of Medicine and Physiology, University of Puerto Rico School
of Medicine and the Cardiovascular Center of Puerto Rico and the Caribbean
| | - José Hernández-Gil de Lamadrid
- All authors: Departments of Medicine and Physiology, University of Puerto Rico School
of Medicine and the Cardiovascular Center of Puerto Rico and the Caribbean
| | - Nelson Escobales
- All authors: Departments of Medicine and Physiology, University of Puerto Rico School
of Medicine and the Cardiovascular Center of Puerto Rico and the Caribbean
| | - María J. Crespo
- All authors: Departments of Medicine and Physiology, University of Puerto Rico School
of Medicine and the Cardiovascular Center of Puerto Rico and the Caribbean
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Crespo MJ, Marrero M, Cruz N, Quidgley J, Creagh O, Torres H, Rivera K. Diabetes alters cardiovascular responses to anaesthetic induction agents in STZ-diabetic rats. Diab Vasc Dis Res 2011; 8:299-302. [PMID: 21933844 DOI: 10.1177/1479164111421035] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND People with diabetes are at increased risk of cardiovascular (CV) morbidity and mortality during surgery. The most appropriate anaesthetic induction agent for these patients is unknown. METHODS AND RESULTS We assessed the CV effects of propofol, etomidate and ketamine in streptozotocin (65 mg/kg, IP) diabetic rats. In non-diabetic rats, none of these anaesthetics significantly modified cardiac output, heart rate or stroke volume, but ketamine increased systolic blood pressure (SBP) compared to etomidate and propofol (89.6 ± 2.4 mmHg, vs. 72.7 ± 3.0 and 75.4 ± 1.9; p < 0.05). In diabetic rats, by contrast, cardiac output was lower with ketamine (82.6 ± 14 ml/min) and etomidate (78.2 ± 15.8 ml/min) than with propofol (146 ± 21 ml/min, N = 8, p < 0.01). SBP, however, was higher in the propofol-treated group (93.3 ± 3.4 mmHg, p < 0.05). CONCLUSION These results suggest that hyperglycaemia modifies CV responses to induction anaesthetics.
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Affiliation(s)
- Maria J Crespo
- Physiology Department, University of Puerto Rico-School of Medicine, San Juan, PR.
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Roe ND, Thomas DP, Ren J. Inhibition of NADPH oxidase alleviates experimental diabetes-induced myocardial contractile dysfunction. Diabetes Obes Metab 2011; 13:465-73. [PMID: 21272185 DOI: 10.1111/j.1463-1326.2011.01369.x] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
AIM O(2) (-) production is implicated in cardiac dysfunction for a number of diseases including diabetes. Activation of the O(2) (-)-producing enzyme NADPH oxidase is seen in diabetes, although its role in diabetic cardiomyopathy is unclear. This study was designed to evaluate the effect of NADPH oxidase inhibition on cardiac function in diabetes. METHODS Experimental diabetes was induced in adult C57 mice using streptozotocin (STZ, 150 mg/kg, i.p.) prior to the administration of the NADPH oxidase inhibitor apocynin (4 mg/kg/day) for 2 weeks. Left ventricular (LV) and myocyte contractile functions were evaluated using echocardiography and edge-detection, respectively. RESULTS STZ elicited hyperglycaemia and reduced body weight gain, which was unaffected by apocynin. STZ significantly reduced fractional shortening, LV wall thickness, peak shortening, maximal velocity and duration of shortening or relengthening, the effects of which - with the exception of wall thickness - were significantly attenuated or ablated by apocynin. Western blot analysis revealed that the effects of comparable Akt phosphorylation, reduced AMPK phosphorylation, downregulation of sarco(endo)plasmic reticulum Ca(2+)-ATPase and lessened phosphorylation of phospholamban in diabetic myocardium were unaffected by apocynin. Both apocynin and the nitric oxide synthase (NOS) inhibitor l-arginine methyl ester (L-NAME) inhibited elevated O(2) (-) production in diabetes without any additive effect between the two, indicating the presence of endothelial nitric oxide synthase (eNOS) uncoupling. However, neither diabetes nor apocynin altered the expression of heat shock protein 90 and eNOS phosphorylation (Ser(1177)). In addition, apocynin mitigated elevated levels of nitrotyrosine and nitric oxide in diabetes. CONCLUSION Taken together, these data indicate the beneficial role of NADPH oxidase inhibition in diabetes-induced myocardial contractile dysfunction.
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Affiliation(s)
- N D Roe
- Division of Pharmaceutical Sciences & Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, USA
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Belkina LM, Terekhina OL, Smirnova EA, Usacheva MA, Kruglov SV, Saltykova VA. Effect of Acute Alloxan Diabetes on Ischemic and Reperfusion Arrhythmias in Rats with Different Activity of Nitric Oxide System. Bull Exp Biol Med 2011; 150:299-303. [DOI: 10.1007/s10517-011-1127-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Matsuki A, Nozawa T, Igarashi N, Sobajima M, Ohori T, Suzuki T, Fujii N, Igawa A, Inoue H. Fluvastatin attenuates diabetes-induced cardiac sympathetic neuropathy in association with a decrease in oxidative stress. Circ J 2010; 74:468-75. [PMID: 20103973 DOI: 10.1253/circj.cj-09-0402] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Increased oxidative stress might contribute to diabetic (DM) neuropathy, so the effects of long-term treatment with fluvastatin (FL) on myocardial oxidative stress and cardiac sympathetic neural function were investigated in diabetic rats. METHODS AND RESULTS FL (10 mg . kg(-1) . day(-1), DM-FL) or vehicle (DM-VE) was orally administered for 2 weeks to streptozotocin-induced DM rats. Cardiac oxidative stress was determined by myocardial 8-iso-prostaglandin F(2alpha) (PGF(2alpha)) and NADPH oxidase subunit p22(phox) mRNA expression. Sympathetic neural function was quantified by autoradiography using (131)I- and (125)I-metaiodobenzylguanidine (MIBG). FL did not affect plasma glucose levels but remarkably decreased PGF(2alpha) levels compared with DM-VE rats (13.8+/-9.2 vs 175.0+/-93.9 ng/g tissue), although PGF(2alpha) levels were below the detection limit in non-DM rats. FL significantly reduced myocardial p22(phox) mRNA expression. Cardiac (131)I-MIBG uptake was lower in DM-VE rats than in non-DM rats, but the decrease was attenuated in DM-FL rats (1.31+/-0.08, 1.88+/-0.22, and 1.58+/-0.18 %kg dose/g, respectively, P<0.01). Cardiac MIBG clearance was not affected by the induction of DM or by FL, indicating that the reduced MIBG uptake in DM rats might result from impaired neural function. CONCLUSIONS FL ameliorates cardiac sympathetic neural dysfunction in DM rats in association with attenuation of increased myocardial oxidative stress.
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Affiliation(s)
- Akira Matsuki
- Second Department of Internal Medicine, Graduate School of Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
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Klimas J, Kmecova J, Jankyova S, Yaghi D, Priesolova E, Kyselova Z, Musil P, Ochodnicky P, Krenek P, Kyselovic J, Matyas S. Pycnogenol®
improves left ventricular function in streptozotocin-induced diabetic cardiomyopathy in rats. Phytother Res 2009; 24:969-74. [PMID: 19957251 DOI: 10.1002/ptr.3015] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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Vareniuk I, Pavlov IA, Obrosova IG. Inducible nitric oxide synthase gene deficiency counteracts multiple manifestations of peripheral neuropathy in a streptozotocin-induced mouse model of diabetes. Diabetologia 2008; 51:2126-33. [PMID: 18802679 PMCID: PMC3044437 DOI: 10.1007/s00125-008-1136-3] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2008] [Accepted: 07/22/2008] [Indexed: 10/21/2022]
Abstract
AIMS/HYPOTHESIS Evidence for the importance of peroxynitrite, a product of superoxide anion radical reaction with nitric oxide, in peripheral diabetic neuropathy is emerging. The role of specific nitric oxide synthase isoforms in diabetes-associated nitrosative stress and nerve fibre dysfunction and degeneration remains unknown. This study evaluated the contribution of inducible nitric oxide synthase (iNOS) to peroxynitrite injury to peripheral nerve and dorsal root ganglia and development of peripheral diabetic neuropathy. METHODS Control mice and mice with iNos (also known as Nos2) gene deficiency (iNos ( -/- )) were made diabetic with streptozotocin, and maintained for 6 weeks. Peroxynitrite injury was assessed by nitrotyrosine and poly(ADP-ribose) accumulation (immunohistochemistry). Thermal algesia was evaluated by paw withdrawal, tail-flick and hot plate tests, mechanical algesia by the Randall-Selitto test, and tactile allodynia by a von Frey filament test. RESULTS Diabetic wild-type mice displayed peroxynitrite injury in peripheral nerve and dorsal root ganglion neurons. They also developed motor and sensory nerve conduction velocity deficits, thermal and mechanical hypoalgesia, tactile allodynia and approximately 36% loss of intraepidermal nerve fibres. Diabetic iNos ( -/- ) mice did not display nitrotyrosine and poly(ADP-ribose) accumulation in peripheral nerve, but were not protected from nitrosative stress in dorsal root ganglia. Despite this latter circumstance, diabetic iNos ( -/- ) mice preserved normal nerve conduction velocities. Small-fibre sensory neuropathy was also less severe in diabetic iNos ( -/- ) than in wild-type mice. CONCLUSIONS/INTERPRETATION iNOS plays a key role in peroxynitrite injury to peripheral nerve, and functional and structural changes of diabetic neuropathy. Nitrosative stress in axons and Schwann cells, rather than dorsal root ganglion neurons, underlies peripheral nerve dysfunction and degeneration.
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Affiliation(s)
- I Vareniuk
- Pennington Biomedical Research Center, Louisiana State University System, LA 70808, USA
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