|
1
|
Pena E, El Alam S, Gonzalez C, Cortés I, Aguilera D, Flores K, Arriaza K. Astaxanthin Supplementation Effects in Right Ventricle of Rats Exposed to Chronic Intermittent Hypobaric Hypoxia. Antioxidants (Basel) 2024; 13:1269. [PMID: 39456521 PMCID: PMC11504862 DOI: 10.3390/antiox13101269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 10/15/2024] [Accepted: 10/17/2024] [Indexed: 10/28/2024] Open
Abstract
In Chile, individuals are commonly exposed to high altitude due to the work shift system, involving days of exposure to high altitude followed by days at sea level over the long term, which can result in chronic intermittent hypobaric hypoxia (CIHH). CIHH can cause high-altitude pulmonary hypertension (HAPH), the principal manifestation of which is right ventricular hypertrophy (RVH), in some cases leading to heart failure and eventually death. Studies have shown the contribution of oxidative stress and inflammation to RVH development. Recently, it was determined that the pigment astaxanthin has high antioxidant capacity and strong anti-inflammatory and cardioprotective effects. Therefore, the aim of this study was to determine the effects of astaxanthin on RVH development in rats subjected to CIHH. METHODS Thirty two male Wistar rats were randomly assigned to the following groups (n = 8 per group): the normoxia with vehicle (NX), normoxia with astaxanthin (NX + AS), chronic intermittent hypobaric hypoxia with vehicle (CIHH), and chronic intermittent hypobaric hypoxia with astaxanthin (CIHH + AS) groups. CIHH was simulated by 2 days in a hypobaric chamber followed by 2 days at sea level for 29 days. RESULTS Exposure to CIHH induced RVH and increased lipid peroxidation (MDA), Nox2 expression, and SOD activity, however, it decreased pro-IL-1β expression. Astaxanthin restored oxidative stress markers (Nox2 and MDA), increased GPx activity, and decreased RVH compared to CIHH. CONCLUSION Astaxanthin alleviates RVH and reduces Nox2 and MDA levels while increasing GPx activity in rats subjected to CIHH. These findings provide new insights of astaxanthin as a new nutraceutical against high-altitude effects.
Collapse
Affiliation(s)
- Eduardo Pena
- High Altitude Medicine Research Center (CEIMA), Arturo Prat University, Iquique 1100000, Chile; (S.E.A.); (C.G.); (D.A.); (K.F.); (K.A.)
| | - Samia El Alam
- High Altitude Medicine Research Center (CEIMA), Arturo Prat University, Iquique 1100000, Chile; (S.E.A.); (C.G.); (D.A.); (K.F.); (K.A.)
| | - Constanza Gonzalez
- High Altitude Medicine Research Center (CEIMA), Arturo Prat University, Iquique 1100000, Chile; (S.E.A.); (C.G.); (D.A.); (K.F.); (K.A.)
| | - Isaac Cortés
- Science Faculty, Arturo Prat University, Iquique 1100000, Chile;
| | - Diego Aguilera
- High Altitude Medicine Research Center (CEIMA), Arturo Prat University, Iquique 1100000, Chile; (S.E.A.); (C.G.); (D.A.); (K.F.); (K.A.)
| | - Karen Flores
- High Altitude Medicine Research Center (CEIMA), Arturo Prat University, Iquique 1100000, Chile; (S.E.A.); (C.G.); (D.A.); (K.F.); (K.A.)
| | - Karem Arriaza
- High Altitude Medicine Research Center (CEIMA), Arturo Prat University, Iquique 1100000, Chile; (S.E.A.); (C.G.); (D.A.); (K.F.); (K.A.)
| |
Collapse
|
|
2
|
Zygmunciak P, Stróżna K, Błażowska O, Mrozikiewicz-Rakowska B. Extracellular Vesicles in Diabetic Cardiomyopathy-State of the Art and Future Perspectives. Int J Mol Sci 2024; 25:6117. [PMID: 38892303 PMCID: PMC11172920 DOI: 10.3390/ijms25116117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 05/24/2024] [Accepted: 05/30/2024] [Indexed: 06/21/2024] Open
Abstract
Cardiovascular complications are the most deadly and cost-driving effects of diabetes mellitus (DM). One of them, which is steadily attracting attention among scientists, is diabetes-induced heart failure, also known as diabetic cardiomyopathy (DCM). Despite significant progress in the research concerning the disease, a universally accepted definition is still lacking. The pathophysiology of the processes accelerating heart insufficiency in diabetic patients on molecular and cellular levels also remains elusive. However, the recent interest concerning extracellular vesicles (EVs) has brought promise to further clarifying the pathological events that lead to DCM. In this review, we sum up recent investigations on the involvement of EVs in DCM and show their therapeutic and indicatory potential.
Collapse
Affiliation(s)
| | - Katarzyna Stróżna
- Faculty of Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland; (P.Z.)
| | - Olga Błażowska
- Faculty of Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland; (P.Z.)
| | - Beata Mrozikiewicz-Rakowska
- Department of Endocrinology, Centre of Postgraduate Medical Education, Marymoncka St. 99/103, 01-813 Warsaw, Poland
| |
Collapse
|
|
3
|
Lee YC, Jou YC, Chou WC, Tsai KL, Shen CH, Lee SD. Ellagic acid protects against angiotensin II-induced hypertrophic responses through ROS-mediated MAPK pathway in H9c2 cells. ENVIRONMENTAL TOXICOLOGY 2024; 39:3253-3263. [PMID: 38356441 DOI: 10.1002/tox.24170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 01/19/2024] [Accepted: 01/26/2024] [Indexed: 02/16/2024]
Abstract
The early myocardial response of hypertension is an elevation of angiotensin-II (Ang-II) concentration, leading to heart failure and cardiac hypertrophy. This hypertrophic event of the heart is mediated by the interaction of Ang type 1 receptors (AT-R1), thereby modulating NADPH oxidase activity in cardiomyocytes, which alters redox status in cardiomyocytes. Ellagic acid (EA) has anti-inflammatory and anti-oxidative capacities. Thus, EA has potential preventive effects on cardiovascular diseases and diabetes. In the last decades, because the protective effect of EA on Ang-II-induced hypertrophic responses is unclear, this study aims to investigate the protective effect of EA in cardiomyocytes. H9c2 cells were treated to Ang-II 1 μM for 24 h to induce cellular damage. We found that EA protected against Ang-II-increased cell surface area and pro-hypertrophic gene expression in H9c2. EA reduced Ang-II-caused AT-R1 upregulation, thereby inhibiting oxidative stress NADPH oxidase activation. EA mitigated Ang-II-enhanced p38 and extracellular-signal-regulated kinase (ERK) phosphorylation. Moreover, EA treatment under Ang-II stimulation also reversed NF-κB activity and iNOS expression. This study shows that EA protects against Ang-II-induced myocardial hypertrophy and attenuates oxidative stress through reactive oxygen species-mediated mitogen-activated protein kinase signaling pathways in H9c2 cells. Thus, EA may be an effective compound for preventing Ang-II-induced myocardial hypertrophy.
Collapse
Affiliation(s)
- Ya-Che Lee
- Department of Urology, Ditmanson Medical Foundation Chiayi Christian Hospital, Chia-Yi City, Taiwan
| | - Yeong-Chin Jou
- Department of Urology, St. Martin De Porres Hospital, Chia-Yi City, Taiwan
- Department of Health and Nutrition Biotechnology, College of Medical and Health Science, Asia University, Taichung City, Taiwan
| | - Wan-Ching Chou
- Department of Physical Therapy, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
| | - Kun-Ling Tsai
- Department of Physical Therapy, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
- Institute of Allied Health Science, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
| | - Cheng-Huang Shen
- Department of Urology, Ditmanson Medical Foundation Chiayi Christian Hospital, Chia-Yi City, Taiwan
- Department of Biomedical Sciences, National Chung Cheng University, Min Hsiung, Chia-Yi, Taiwan
| | - Shin-Da Lee
- Department of Physical Therapy, College of Medical and Health Science, Asia University, Taichung City, Taiwan
- Department of Physical Therapy, PhD program in Healthcare Science, China Medical University, Taichung, Taiwan
| |
Collapse
|
|
4
|
Wen J, Liu G, Liu M, Wang H, Wan Y, Yao Z, Gao N, Sun Y, Zhu L. Transforming growth factor-β and bone morphogenetic protein signaling pathways in pathological cardiac hypertrophy. Cell Cycle 2023; 22:2467-2484. [PMID: 38179789 PMCID: PMC10802212 DOI: 10.1080/15384101.2023.2293595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 09/22/2023] [Accepted: 10/09/2023] [Indexed: 01/06/2024] Open
Abstract
Pathological cardiac hypertrophy (referred to as cardiac hypertrophy) is a maladaptive response of the heart to a variety of pathological stimuli, and cardiac hypertrophy is an independent risk factor for heart failure and sudden death. Currently, the treatments for cardiac hypertrophy are limited to improving symptoms and have little effect. Elucidation of the developmental process of cardiac hypertrophy at the molecular level and the identification of new targets for the treatment of cardiac hypertrophy are crucial. In this review, we summarize the research on multiple active substances related to the pathogenesis of cardiac hypertrophy and the signaling pathways involved and focus on the role of transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signaling in the development of cardiac hypertrophy and the identification of potential targets for molecular intervention. We aim to identify important signaling molecules with clinical value and hope to help promote the precise treatment of cardiac hypertrophy and thus improve patient outcomes.
Collapse
Affiliation(s)
- Jing Wen
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Guixiang Liu
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Mingjie Liu
- Department of Lung Function, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Huarui Wang
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Yunyan Wan
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Zhouhong Yao
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Nannan Gao
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Yuanyuan Sun
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Ling Zhu
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| |
Collapse
|
|
5
|
Gul R, Dar MA, Nawaz S, Alfadda AA. Protective Effects of Nanoceria against Mitochondrial Dysfunction and Angiotensin II-Induced Hypertrophy in H9c2 Cardiomyoblasts. Antioxidants (Basel) 2023; 12:antiox12040877. [PMID: 37107252 PMCID: PMC10135342 DOI: 10.3390/antiox12040877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 03/27/2023] [Accepted: 03/29/2023] [Indexed: 04/08/2023] Open
Abstract
Mitochondrial dysfunction triggered by increased reactive oxygen species (ROS) generation is involved in the pathogenesis and development of cardiac hypertrophy. Nanoceria (cerium oxide nanoparticle) has powerful ROS-scavenging properties and is considered a potential therapeutic option for curbing ROS-related disorders. Here, we explored the signaling mechanism underlying the protective effects of nanoceria against angiotensin (Ang) II-stimulated pathological response in H9c2 cardiomyoblasts. Our data revealed that pretreatment of H9c2 cardiomyoblasts with nanoceria significantly prevented Ang II-stimulated generation of intracellular ROS, aberrant expression of pro-inflammatory cytokines, and hypertrophy markers. Nanoceria pretreatment increased the mRNA levels of genes regulating the cellular antioxidant defense system (SOD2, MnSOD, CAT) in Ang II-treated cells. Furthermore, nanoceria restored mitochondrial function by decreasing mitochondrial ROS, increasing mitochondrial membrane potential (MMP), and promoting the mRNA expression of genes associated with mitochondrial biogenesis (PGC-1α, TFAM, NRF1, and SIRT3) and mitochondrial fusion (MFN2, OPA1). Collectively, these findings demonstrate the protective effects of nanoceria against Ang II-mediated mitochondrial dysfunction and pathological hypertrophy in H9c2 cells.
Collapse
Affiliation(s)
- Rukhsana Gul
- Obesity Research Center, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia
| | - Mushtaq A. Dar
- Center of Excellence for Research in Engineering Materials (CEREM), Deanship of Scientific Research (DSR), King Saudi University, Riyadh 11421, Saudi Arabia
| | - Shahid Nawaz
- Obesity Research Center, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia
| | - Assim A. Alfadda
- Obesity Research Center, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia
- Department of Medicine, College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia
| |
Collapse
|
|
6
|
Gul R, Alsalman N, Alfadda AA. Inhibition of eNOS Partially Blunts the Beneficial Effects of Nebivolol on Angiotensin II-Induced Signaling in H9c2 Cardiomyoblasts. Curr Issues Mol Biol 2022; 44:2139-2152. [PMID: 35678673 PMCID: PMC9164031 DOI: 10.3390/cimb44050144] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 04/21/2022] [Accepted: 04/28/2022] [Indexed: 11/26/2022] Open
Abstract
We have recently illustrated that nebivolol can inhibit angiotensin II (Ang II)-mediated signaling in cardiomyoblasts; however, to date, the detailed mechanism for the beneficial effects of nebivolol has not been studied. Here, we investigated whether the inhibition of NO bioavailability by blocking eNOS (endothelial nitric oxide synthase) using L-NG-nitroarginine methyl ester (L-NAME) would attenuate nebivolol-mediated favorable effects on Ang II-evoked signaling in H9c2 cardiomyoblasts. Our data reveal that the nebivolol-mediated antagonistic effects on Ang II-induced oxidative stress were retreated by concurrent pretreatment with L-NAME and nebivolol. Similarly, the expressions of pro-inflammatory markers TNF-α and iNOS stimulated by Ang II were not decreased with the combination of nebivolol plus L-NAME. In contrast, the nebivolol-induced reduction in the Ang II-triggered mTORC1 pathway and the mRNA levels of hypertrophic markers ANP, BNP, and β-MHC were not reversed with the addition of L-NAME to nebivolol. In compliance with these data, the inhibition of eNOS by L-N⁵-(1-Iminoethyl) ornithine (LNIO) and its upstream regulator AMP-activated kinase (AMPK) with compound C in the presence of nebivolol showed effects similar to those of the L-NAME plus nebivolol combination on Ang II-mediated signaling. Pretreatment with either compound C plus nebivolol or LNIO plus nebivolol showed similar effects to those of the L-NAME plus nebivolol combination on Ang II-mediated signaling. In conclusion, our data indicate that the rise in NO bioavailability caused by nebivolol via the stimulation of AMPK/eNOS signaling is key for its anti-inflammatory and antioxidant properties but not for its antihypertrophic response upon Ang II stimulation.
Collapse
Affiliation(s)
- Rukhsana Gul
- Obesity Research Center, College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia; (N.A.); (A.A.A.)
| | - Nouf Alsalman
- Obesity Research Center, College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia; (N.A.); (A.A.A.)
| | - Assim A. Alfadda
- Obesity Research Center, College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia; (N.A.); (A.A.A.)
- Department of Medicine, College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia
- Strategic Center for Diabetes Research, College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia
| |
Collapse
|
|
7
|
Roles of cADPR and NAADP in pancreatic beta cell signalling. Cell Calcium 2022; 103:102562. [DOI: 10.1016/j.ceca.2022.102562] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 02/05/2022] [Accepted: 02/09/2022] [Indexed: 11/19/2022]
|
|
8
|
Hwang JS, Hur J, Lee WJ, Won JP, Lee HG, Lim DS, Kim E, Seo HG. Catalase Mediates the Inhibitory Actions of PPARδ against Angiotensin II-Triggered Hypertrophy in H9c2 Cardiomyocytes. Antioxidants (Basel) 2021; 10:antiox10081223. [PMID: 34439471 PMCID: PMC8388952 DOI: 10.3390/antiox10081223] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/23/2021] [Accepted: 07/26/2021] [Indexed: 01/05/2023] Open
Abstract
Hypertrophy of myocytes has been implicated in cardiac dysfunctions affecting wall stress and patterns of gene expression. However, molecular targets potentially preventing cardiac hypertrophy have not been fully elucidated. In the present study, we demonstrate that upregulation of catalase by peroxisome proliferator-activated receptor δ (PPARδ) is involved in the anti-hypertrophic activity of PPARδ in angiotensin II (Ang II)-treated H9c2 cardiomyocytes. Activation of PPARδ by a specific ligand GW501516 significantly inhibited Ang II-induced hypertrophy and the generation of reactive oxygen species (ROS) in H9c2 cardiomyocytes. These effects of GW501516 were almost completely abolished in cells stably expressing small hairpin (sh)RNA targeting PPARδ, indicating that PPARδ mediates these effects. Significant concentration and time-dependent increases in catalase at both mRNA and protein levels were observed in GW501516-treated H9c2 cardiomyocytes. In addition, GW501516-activated PPARδ significantly enhanced catalase promoter activity and protein expression, even in the presence of Ang II. GW501516-activated PPARδ also inhibited the expression of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), which are both marker proteins for hypertrophy. The effects of GW501516 on the expression of ANP and BNP were reversed by 3-amino-1,2,4-triazole (3-AT), a catalase inhibitor. Inhibition or downregulation of catalase by 3-AT or small interfering (si)RNA, respectively, abrogated the effects of PPARδ on Ang II-induced hypertrophy and ROS generation, indicating that these effects of PPARδ are mediated through catalase induction. Furthermore, GW501516-activated PPARδ exerted catalase-dependent inhibitory effects on Ang II-induced hypertrophy by blocking p38 mitogen-activated protein kinase. Taken together, these results indicate that the anti-hypertrophic activity of PPARδ may be achieved, at least in part, by sequestering ROS through fine-tuning the expression of catalase in cardiomyocytes.
Collapse
Affiliation(s)
- Jung Seok Hwang
- College of Sang-Huh Life Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea; (J.S.H.); (J.H.); (W.J.L.); (J.P.W.); (H.G.L.); (E.K.)
| | - Jinwoo Hur
- College of Sang-Huh Life Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea; (J.S.H.); (J.H.); (W.J.L.); (J.P.W.); (H.G.L.); (E.K.)
| | - Won Jin Lee
- College of Sang-Huh Life Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea; (J.S.H.); (J.H.); (W.J.L.); (J.P.W.); (H.G.L.); (E.K.)
| | - Jun Pil Won
- College of Sang-Huh Life Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea; (J.S.H.); (J.H.); (W.J.L.); (J.P.W.); (H.G.L.); (E.K.)
| | - Hyuk Gyoon Lee
- College of Sang-Huh Life Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea; (J.S.H.); (J.H.); (W.J.L.); (J.P.W.); (H.G.L.); (E.K.)
| | - Dae-Seog Lim
- Department of Biotechnology, CHA University, 355 Pangyo-ro, Bundang-gu, Seongnam 13488, Korea;
| | - Eunsu Kim
- College of Sang-Huh Life Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea; (J.S.H.); (J.H.); (W.J.L.); (J.P.W.); (H.G.L.); (E.K.)
| | - Han Geuk Seo
- College of Sang-Huh Life Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea; (J.S.H.); (J.H.); (W.J.L.); (J.P.W.); (H.G.L.); (E.K.)
- Correspondence: ; Tel.: +82-2-450-0428; Fax: +82-2-455-1044
| |
Collapse
|
|
9
|
Gul R, Kim UH, Alfadda AA. Renin-angiotensin system at the interface of COVID-19 infection. Eur J Pharmacol 2021; 890:173656. [PMID: 33086029 PMCID: PMC7568848 DOI: 10.1016/j.ejphar.2020.173656] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 10/07/2020] [Accepted: 10/16/2020] [Indexed: 11/30/2022]
Abstract
Angiotensin-converting enzyme 2 (ACE2) has been recognized as a potential entry receptor for SARS-CoV-2 infection. Binding of SARS-CoV-2 to ACE2 allows engagement with pulmonary epithelial cells and pulmonary infection with the virus. ACE2 is an essential component of renin-angiotensin system (RAS), and involved in promoting protective effects to counter-regulate angiotensin (Ang) II-induced pathogenesis. The use of angiotensin receptor blockers (ARBs) and ACE inhibitors (ACEIs) was implicitly negated during the early phase of COVID-19 pandemic, considering the role of these antihypertensive agents in enhancing ACE2 expression thereby promoting the susceptibility to SARS-CoV-2. However, no clinical data has supported this assumption, but indeed evidence demonstrates that ACEIs and ARBs, besides their cardioprotective effects in COVID-19 patients with cardiovascular diseases, might also be beneficial in acute lung injuries by preserving the ACE2 function and switching the balance from deleterious ACE/Ang II/AT1 receptor axis towards a protective ACE2/Ang (1-7)/Mas receptor axis.
Collapse
Affiliation(s)
- Rukhsana Gul
- Obesity Research Center, College of Medicine, King Saud University, P.O. Box 2925, Riyadh, 11461, Saudi Arabia.
| | - Uh-Hyun Kim
- Department of Biochemistry & National Creative Research Laboratory for Ca(2+) Signaling, Chonbuk National University Medical School, Jeonju, 54907, Republic of Korea
| | - Assim A Alfadda
- Obesity Research Center, College of Medicine, King Saud University, P.O. Box 2925, Riyadh, 11461, Saudi Arabia; Department of Medicine, College of Medicine, King Saud University, PO Box 2925, Riyadh, 11461, Saudi Arabia; Strategic Center for Diabetes Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| |
Collapse
|
|
10
|
Samstag Y, Bogert NV, Wabnitz GH, Din S, Therre M, Leuschner F, Katus HA, Konstandin MH. Reactive Oxidative Species-Modulated Ca 2+ Release Regulates β 2 Integrin Activation on CD4 + CD28 null T Cells of Acute Coronary Syndrome Patients. THE JOURNAL OF IMMUNOLOGY 2020; 205:2276-2286. [PMID: 32938726 DOI: 10.4049/jimmunol.2000327] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Accepted: 08/17/2020] [Indexed: 01/06/2023]
Abstract
The number and activity of T cell subsets in the atherosclerotic plaques are critical for the prognosis of patients with acute coronary syndrome. β2 Integrin activation is pivotal for T cell recruitment and correlates with future cardiac events. Despite this knowledge, differential regulation of adhesiveness in T cell subsets has not been explored yet. In this study, we show that in human T cells, SDF-1α-mediated β2 integrin activation is driven by a, so far, not-described reactive oxidative species (ROS)-regulated calcium influx. Furthermore, we show that CD4+CD28null T cells represent a highly reactive subset showing 25-fold stronger β2 integrin activation upon SDF-1α stimulation compared with CD28+ T cells. Interestingly, ROS-dependent Ca release was much more prevalent in the pathogenetically pivotal CD28null subset compared with the CD28+ T cells, whereas the established mediators of the classical pathways for β2 integrin activation (PKC, PI3K, and PLC) were similarly activated in both T cell subsets. Thus, interference with the calcium flux attenuates spontaneous adhesion of CD28null T cells from acute coronary syndrome patients, and calcium ionophores abolished the observed differences in the adhesion properties between CD28+ and CD28null T cells. Likewise, the adhesion of these T cell subsets was indistinguishable in the presence of exogenous ROS/H2O2 Together, these data provide a molecular explanation of the role of ROS in pathogenesis of plaque destabilization.
Collapse
Affiliation(s)
- Yvonne Samstag
- Institute of Immunology, Section Molecular Immunology, Ruprecht-Karls-University, D-69120 Heidelberg, Germany
| | - Nicolai V Bogert
- Department of Cardiology, Heidelberg University Hospital, Ruprecht-Karls-University, D-69120 Heidelberg, Germany; and.,German Centre for Cardiovascular Research Partner Site Heidelberg/Mannheim, Germany, Heidelberg University Hospital, D-69120 Heidelberg, Germany
| | - Guido H Wabnitz
- Institute of Immunology, Section Molecular Immunology, Ruprecht-Karls-University, D-69120 Heidelberg, Germany
| | - Shabana Din
- Department of Cardiology, Heidelberg University Hospital, Ruprecht-Karls-University, D-69120 Heidelberg, Germany; and.,German Centre for Cardiovascular Research Partner Site Heidelberg/Mannheim, Germany, Heidelberg University Hospital, D-69120 Heidelberg, Germany
| | - Markus Therre
- Department of Cardiology, Heidelberg University Hospital, Ruprecht-Karls-University, D-69120 Heidelberg, Germany; and.,German Centre for Cardiovascular Research Partner Site Heidelberg/Mannheim, Germany, Heidelberg University Hospital, D-69120 Heidelberg, Germany
| | - Florian Leuschner
- Department of Cardiology, Heidelberg University Hospital, Ruprecht-Karls-University, D-69120 Heidelberg, Germany; and.,German Centre for Cardiovascular Research Partner Site Heidelberg/Mannheim, Germany, Heidelberg University Hospital, D-69120 Heidelberg, Germany
| | - Hugo A Katus
- Department of Cardiology, Heidelberg University Hospital, Ruprecht-Karls-University, D-69120 Heidelberg, Germany; and.,German Centre for Cardiovascular Research Partner Site Heidelberg/Mannheim, Germany, Heidelberg University Hospital, D-69120 Heidelberg, Germany
| | - Mathias H Konstandin
- Department of Cardiology, Heidelberg University Hospital, Ruprecht-Karls-University, D-69120 Heidelberg, Germany; and .,German Centre for Cardiovascular Research Partner Site Heidelberg/Mannheim, Germany, Heidelberg University Hospital, D-69120 Heidelberg, Germany
| |
Collapse
|
|
11
|
Abstract
The aim of this chapter is to discuss evidence concerning the many roles of calcium ions, Ca2+, in cell signaling pathways that control heart function. Before considering details of these signaling pathways, the control of contraction in ventricular muscle by Ca2+ transients accompanying cardiac action potentials is first summarized, together with a discussion of how myocytes from the atrial and pacemaker regions of the heart diverge from this basic scheme. Cell signaling pathways regulate the size and timing of the Ca2+ transients in the different heart regions to influence function. The simplest Ca2+ signaling elements involve enzymes that are regulated by cytosolic Ca2+. Particularly important examples to be discussed are those that are stimulated by Ca2+, including Ca2+-calmodulin-dependent kinase (CaMKII), Ca2+ stimulated adenylyl cyclases, Ca2+ stimulated phosphatase and NO synthases. Another major aspect of Ca2+ signaling in the heart concerns actions of the Ca2+ mobilizing agents, inositol trisphosphate (IP3), cADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate, (NAADP). Evidence concerning roles of these Ca2+ mobilizing agents in different regions of the heart is discussed in detail. The focus of the review will be on short term regulation of Ca2+ transients and contractile function, although it is recognized that Ca2+ regulation of gene expression has important long term functional consequences which will also be briefly discussed.
Collapse
|
|
12
|
The Essential Role of Ca 2+ Signals in UVB-Induced IL-1β Secretion in Keratinocytes. J Invest Dermatol 2018; 139:1362-1372. [PMID: 30578820 DOI: 10.1016/j.jid.2018.12.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 12/03/2018] [Accepted: 12/05/2018] [Indexed: 12/24/2022]
Abstract
UVB-induced skin damage is attributable to reactive oxygen species, which are triggered by intracellular Ca2+ signals. However, exactly how the reactive oxygen species are triggered by intracellular Ca2+ upon UVB irradiation remains obscure. Here, we show that UVB induces Ca2+ signals via sequential generation of the following Ca2+ messengers: inositol 1,4,5-trisphosphate, nicotinic acid adenine dinucleotide phosphate, and cyclic ADP-ribose. UVB induced H2O2 production through NADPH oxidase 4 activation, which is downstream to inositol 1,4,5-trisphosphate and nicotinic acid adenine dinucleotide phosphate. H2O2 derived from NADPH oxidase 4 activated CD38 to produce cyclic ADP-ribose. UVB first evoked the pannexin channel to release ATP, which acts on P2X7 receptor to generate inositol 1,4,5-trisphosphate. Inhibitors of these messengers, as well as antioxidants, blocked UVB-induced Ca2+ signals and IL-1β secretion in keratinocytes. Furthermore, ablation of CD38 and NADPH oxidase 4 protected against UVB-induced inflammation and IL-1β secretion in the murine epidermis. These results show that UVB induces IL-1β secretion through cross-talk between Ca2+ and reactive oxygen species, providing insight towards potential targets against UVB-induced inflammation.
Collapse
|
|
13
|
Park DR, Nam TS, Kim YW, Bae YS, Kim UH. Oxidative activation of type III CD38 by NADPH oxidase-derived hydrogen peroxide in Ca 2+ signaling. FASEB J 2018; 33:3404-3419. [PMID: 30452880 DOI: 10.1096/fj.201800235r] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Reactive oxygen species (ROS) derived from NADPH oxidase (Nox) has been shown to activate ADP-ribosyl cyclase (ARC), which produces the Ca2+ mobilizing second messenger, cyclic ADP-ribose (cADPR). In the present study, we examined how ROS activates cluster of differentiation (CD)38, a mammalian prototype of ARC. CD38 exists in type II and III forms with opposing membrane orientation. This study showed the coexpression of type II and III CD38 in lymphokine-activated killer (LAK) cells. The catalytic site of the constitutively active type II CD38 faces the outside of the cell or the inside of early endosomes (EEs), whereas the basally inactive type III CD38 faces the cytosol. Type III CD38 interacted with Nox4/phosphorylated-p22phox (p-p22phox) in EEs of LAK cells upon IL-8 treatment. H2O2 derived from Nox4 activated type III CD38 by forming a disulfide bond between Cys164 and Cys177, resulting in increased cADPR formation. Our study identified the mechanism by which type III CD38 is activated in an immune cell (LAK), in which H2O2 generated by Nox4 oxidizes and activates type III CD38 to generate cADPR. These findings provide a novel model of cross-talk between ROS and Ca2+ signaling.-Park, D.-R., Nam, T.-S., Kim, Y.-W., Bae, Y. S., Kim, U.-H. Oxidative activation of type III CD38 by NADPH oxidase-derived hydrogen peroxide in Ca2+ signaling.
Collapse
Affiliation(s)
- Dae-Ryoung Park
- Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Korea.,National Creative Research Laboratory for Ca2+ Signaling Network, Chonbuk National University Medical School, Jeonju, Korea
| | - Tae-Sik Nam
- Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Korea.,National Creative Research Laboratory for Ca2+ Signaling Network, Chonbuk National University Medical School, Jeonju, Korea
| | - Ye-Won Kim
- Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Korea.,National Creative Research Laboratory for Ca2+ Signaling Network, Chonbuk National University Medical School, Jeonju, Korea
| | - Yun Soo Bae
- Department of Life Science, College of Natural Sciences, Ewha Womans University, Seoul, Korea; and
| | - Uh-Hyun Kim
- Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Korea.,National Creative Research Laboratory for Ca2+ Signaling Network, Chonbuk National University Medical School, Jeonju, Korea.,Institute of Cardiovascular Research, Chonbuk National University Medical School, Jeonju, Korea
| |
Collapse
|
|
14
|
Matic A, Jukic I, Stupin A, Baric L, Mihaljevic Z, Unfirer S, Tartaro Bujak I, Mihaljevic B, Lombard JH, Drenjancevic I. High salt intake shifts the mechanisms of flow-induced dilation in the middle cerebral arteries of Sprague-Dawley rats. Am J Physiol Heart Circ Physiol 2018; 315:H718-H730. [DOI: 10.1152/ajpheart.00097.2018] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The goal of the present study was to examine the effect of 1 wk of high salt (HS) intake and the role of oxidative stress in changing the mechanisms of flow-induced dilation (FID) in isolated pressurized middle cerebral arteries of male Sprague-Dawley rats ( n = 15–16 rats/group). Reduced FID in the HS group was restored by intake of the superoxide scavenger tempol (HS + tempol in vivo group). The nitric oxide (NO) synthase inhibitor Nω-nitro-l-arginine methyl ester, cyclooxygenase inhibitor indomethacin, and selective inhibitor of microsomal cytochrome P-450 epoxidase activity N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide significantly reduced FID in the low salt diet-fed group, whereas FID in the HS group was mediated by NO only. Cyclooxygenase-2 mRNA (but not protein) expression was decreased in the HS and HS + tempol in vivo groups. Hypoxia-inducible factor-1α and VEGF protein levels were increased in the HS group but decreased in the HS + tempol in vivo group. Assessment by direct fluorescence of middle cerebral arteries under flow revealed significantly reduced vascular NO levels and increased superoxide/reactive oxygen species levels in the HS group. These results suggest that HS intake impairs FID and changes FID mechanisms to entirely NO dependent, in contrast to the low-salt diet-fed group, where FID is NO, prostanoid, and epoxyeicosatrienoic acid dependent. These changes were accompanied by increased lipid peroxidation products in the plasma of HS diet-fed rats, increased vascular superoxide/reactive oxygen species levels, and decreased NO levels, together with increased expression of hypoxia-inducible factor-1α and VEGF. NEW & NOTEWORTHY High-salt (HS) diet changes the mechanisms of flow-induced dilation in rat middle cerebral arteries from a combination of nitric oxide-, prostanoid-, and epoxyeicosatrienoic acid-dependent mechanisms to, albeit reduced, a solely nitric oxide-dependent dilation. In vivo reactive oxygen species scavenging restores flow-induced dilation in HS diet-fed rats and ameliorates HS-induced increases in the transcription factor hypoxia-inducible factor-1α and expression of its downstream target genes.
Collapse
Affiliation(s)
- Anita Matic
- Department of Physiology and Immunology, Faculty of Medicine Osijek, Josip Juraj Strossmayer of Osijek, Osijek, Croatia
| | - Ivana Jukic
- Department of Physiology and Immunology, Faculty of Medicine Osijek, Josip Juraj Strossmayer of Osijek, Osijek, Croatia
| | - Ana Stupin
- Department of Physiology and Immunology, Faculty of Medicine Osijek, Josip Juraj Strossmayer of Osijek, Osijek, Croatia
| | - Lidija Baric
- Department of Physiology and Immunology, Faculty of Medicine Osijek, Josip Juraj Strossmayer of Osijek, Osijek, Croatia
| | - Zrinka Mihaljevic
- Department of Physiology and Immunology, Faculty of Medicine Osijek, Josip Juraj Strossmayer of Osijek, Osijek, Croatia
| | - Sanela Unfirer
- Department of Physiology and Immunology, Faculty of Medicine Osijek, Josip Juraj Strossmayer of Osijek, Osijek, Croatia
| | - Ivana Tartaro Bujak
- Radiation Chemistry and Dosimetry Laboratory, Division of Materials Chemistry, Ruđer Bošković Institute, Zagreb, Croatia
| | - Branka Mihaljevic
- Radiation Chemistry and Dosimetry Laboratory, Division of Materials Chemistry, Ruđer Bošković Institute, Zagreb, Croatia
| | - Julian H. Lombard
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Ines Drenjancevic
- Department of Physiology and Immunology, Faculty of Medicine Osijek, Josip Juraj Strossmayer of Osijek, Osijek, Croatia
| |
Collapse
|
|
15
|
Peña-Oyarzun D, Bravo-Sagua R, Diaz-Vega A, Aleman L, Chiong M, Garcia L, Bambs C, Troncoso R, Cifuentes M, Morselli E, Ferreccio C, Quest AFG, Criollo A, Lavandero S. Autophagy and oxidative stress in non-communicable diseases: A matter of the inflammatory state? Free Radic Biol Med 2018; 124:61-78. [PMID: 29859344 DOI: 10.1016/j.freeradbiomed.2018.05.084] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Revised: 05/22/2018] [Accepted: 05/28/2018] [Indexed: 12/11/2022]
Abstract
Non-communicable diseases (NCDs), also known as chronic diseases, are long-lasting conditions that affect millions of people around the world. Different factors contribute to their genesis and progression; however they share common features, which are critical for the development of novel therapeutic strategies. A persistently altered inflammatory response is typically observed in many NCDs together with redox imbalance. Additionally, dysregulated proteostasis, mainly derived as a consequence of compromised autophagy, is a common feature of several chronic diseases. In this review, we discuss the crosstalk among inflammation, autophagy and oxidative stress, and how they participate in the progression of chronic diseases such as cancer, cardiovascular diseases, obesity and type II diabetes mellitus.
Collapse
Affiliation(s)
- Daniel Peña-Oyarzun
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Instituto de Investigación en Ciencias Odontológicas (ICOD), Facultad de Odontología, Universidad de Chile, Santiago, Chile
| | - Roberto Bravo-Sagua
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile
| | - Alexis Diaz-Vega
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Center for Studies of Exercise, Metabolism and Cancer Studies (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Larissa Aleman
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Mario Chiong
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Center for Studies of Exercise, Metabolism and Cancer Studies (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Lorena Garcia
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Center for Studies of Exercise, Metabolism and Cancer Studies (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Claudia Bambs
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; Departamento de Salud Pública, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Rodrigo Troncoso
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile
| | - Mariana Cifuentes
- Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile; Center for Studies of Exercise, Metabolism and Cancer Studies (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Eugenia Morselli
- Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Catterina Ferreccio
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; Departamento de Salud Pública, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Andrew F G Quest
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Center for Studies of Exercise, Metabolism and Cancer Studies (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Alfredo Criollo
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Instituto de Investigación en Ciencias Odontológicas (ICOD), Facultad de Odontología, Universidad de Chile, Santiago, Chile.
| | - Sergio Lavandero
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Center for Studies of Exercise, Metabolism and Cancer Studies (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Cardiology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
| |
Collapse
|
|
16
|
Specific cyclic ADP-ribose phosphohydrolase obtained by mutagenic engineering of Mn 2+-dependent ADP-ribose/CDP-alcohol diphosphatase. Sci Rep 2018; 8:1036. [PMID: 29348648 PMCID: PMC5773619 DOI: 10.1038/s41598-017-18393-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Accepted: 12/12/2017] [Indexed: 01/16/2023] Open
Abstract
Cyclic ADP-ribose (cADPR) is a messenger for Ca2+ mobilization. Its turnover is believed to occur by glycohydrolysis to ADP-ribose. However, ADP-ribose/CDP-alcohol diphosphatase (ADPRibase-Mn) acts as cADPR phosphohydrolase with much lower efficiency than on its major substrates. Recently, we showed that mutagenesis of human ADPRibase-Mn at Phe37, Leu196 and Cys253 alters its specificity: the best substrate of the mutant F37A + L196F + C253A is cADPR by a short difference, Cys253 mutation being essential for cADPR preference. Its proximity to the 'northern' ribose of cADPR in docking models indicates Cys253 is a steric constraint for cADPR positioning. Aiming to obtain a specific cADPR phosphohydrolase, new mutations were tested at Asp250, Val252, Cys253 and Thr279, all near the 'northern' ribose. First, the mutant F37A + L196F + C253G, with a smaller residue 253 (Ala > Gly), showed increased cADPR specificity. Then, the mutant F37A + L196F + V252A + C253G, with another residue made smaller (Val > Ala), displayed the desired specificity, with cADPR kcat/KM ≈20-200-fold larger than for any other substrate. When tested in nucleotide mixtures, cADPR was exhausted while others remained unaltered. We suggest that the specific cADPR phosphohydrolase, by cell or organism transgenesis, or the designed mutations, by genome editing, provide opportunities to study the effect of cADPR depletion on the many systems where it intervenes.
Collapse
|
|
17
|
Feng Q, Lu C, Wang L, Song L, Li C, Uppada RC. Effects of renal denervation on cardiac oxidative stress and local activity of the sympathetic nervous system and renin-angiotensin system in acute myocardial infracted dogs. BMC Cardiovasc Disord 2017; 17:65. [PMID: 28212603 PMCID: PMC5316157 DOI: 10.1186/s12872-017-0498-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 02/09/2017] [Indexed: 02/04/2023] Open
Abstract
Background This study sought to evaluate the therapeutic effects of renal denervation (RDN) on acute myocardial infarction (MI) in canines and explore its possible mechanisms of action. Methods Eighteen healthy mongrel dogs were randomly assigned to either the control group, the MI group or the MI + RDN group. To assess cardiac function, left ventricular ejection fraction (LVEF), left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD) and fraction shortening (FS) were recorded. Additionally, haemodynamic parameters such as left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP) and heart rate (HR) were measured. Cardiac oxidative stress levels were evaluated based on the expression of p47phox mRNA, malondialdehyde (MDA), anti-superoxide anion free radical (ASAFR) and activity of superoxide dismutase (SOD). To measure the local activity of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS), the levels of tyrosine hydroxylase (TH), angiotensin II (AngII), angiotensin-converting enzyme 2 (ACE2), angiotensin (1–7) [Ang(1–7)] and Mas receptor (MasR) in myocardial tissues were recorded. The expression of TH in renal tissue and serum creatinine were used to assess the effectiveness of the RDN procedure and renal function, respectively. Results We found that MI deteriorated heart function and activated cardiac oxidative stress and the local neurohumoral system, while RDN partially reversed these changes. Compared with the control group, parameters including LVEDD, LVESD, LVEDP and the levels of ASAFR, MDA, p47phox,ACE2, Ang(1–7), MasR, AngII and TH-positive nerves were increased (all P < 0.05) in myocardial infracted dogs; meanwhile, LVEF, FS, LVSP and SOD expression were decreased (all P < 0.05). However, after RDN therapy, these changes were significantly improved (P < 0.05), except that there were no significant differences observed in FS or LVSP between the two groups (P = 0.092 and 0.931, respectively). Importantly, the expression of TH, AngII and Ang(1–7) was positively correlated with MDA and negatively correlated with SOD. Between-group comparisons demonstrated no differences in serum creatinine (P = 0.706). Conclusions RDN attenuated cardiac remodelling and improved heart function by decreasing the level of cardiac oxidative stress and the local activity of the SNS and RAS in cardiac tissues. Additionally, the safety of the RDN procedure was established, as no significant decrease in LVSP or rise in serum creatinine was observed in our study.
Collapse
Affiliation(s)
- Qiaoli Feng
- First Center Clinic College of Tianjin Medical University, Tianjin First Central Hospital, Tianjin, China
| | - Chengzhi Lu
- Department of Cardiology, Tianjin First Central Hospital, 24 Fukang Road, Nankai District, Tianjin, 300192, China.
| | - Li Wang
- Department of Cardiology, Tianjin First Central Hospital, 24 Fukang Road, Nankai District, Tianjin, 300192, China
| | - Lijun Song
- Department of Digestion, Tianjin First Central Hospital, Tianjin, China
| | - Chao Li
- Department of Cardiology, Tianjin First Central Hospital, 24 Fukang Road, Nankai District, Tianjin, 300192, China
| | - Ravi Chandra Uppada
- First Center Clinic College of Tianjin Medical University, Tianjin First Central Hospital, Tianjin, China
| |
Collapse
|
|
18
|
Maiolino G, Azzolini M, Rossi GP, Davis PA, Calò LA. Bartter/Gitelman syndromes as a model to study systemic oxidative stress in humans. Free Radic Biol Med 2015; 88:51-8. [PMID: 25770663 DOI: 10.1016/j.freeradbiomed.2015.02.037] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Revised: 02/24/2015] [Accepted: 02/26/2015] [Indexed: 02/07/2023]
Abstract
Reactive oxygen species (ROS) are intermediates in reduction-oxidation reactions that begin with the addition of one electron to molecular oxygen, generating the primary ROS superoxide, which in turn interacts with other molecules to produce secondary ROS, such as hydrogen peroxide, hydroxyl radical, and peroxynitrite. ROS are continuously produced during metabolic processes and are deemed to play an important role in cardiovascular diseases, namely, myocardial hypertrophy and fibrosis and atherosclerosis, via oxidative damage of lipids, proteins, and deoxyribonucleic acid. Angiotensin II (Ang II) is a potent vasoactive agent that also exerts mitogenic, proinflammatory, and profibrotic effects through several signaling pathways, in part involving ROS, particularly superoxide and hydrogen peroxide. Moreover, Ang II stimulates NADPH oxidases, leading to higher ROS generation and oxidative stress. Bartter/Gitelman syndrome patients, despite elevated plasma renin activity, Ang II, and aldosterone levels, exhibit reduced peripheral resistance, normal/low blood pressure, and blunted pressor effect of vasoconstrictors. In addition, notwithstanding the activation of the renin-angiotensin system and the increased plasma levels of Ang II, these patients display decreased production of ROS, reduced oxidative stress, and increased antioxidant defenses. In fact, Bartter/Gitelman syndrome patients are characterized by reduced levels of p22(phox) gene expression and undetectable plasma peroxynitrite levels, while showing increased plasma antioxidant power and expression of antioxidant enzymes, such as heme oxygenase-1. In conclusion, multifarious data suggest that Bartter and Gitelman syndrome patients are a model of low oxidative stress and high antioxidant defenses. The contribution offered by the study of these syndromes in elucidating the molecular mechanisms underlying this favorable status could offer chances for new therapeutic targets in disease characterized by high levels of reactive oxygen species.
Collapse
Affiliation(s)
- Giuseppe Maiolino
- Nephrology and Hypertension Clinic, Department of Medicine, University of Padova, 35126 Padova, Italy
| | - Matteo Azzolini
- Nephrology and Hypertension Clinic, Department of Medicine, University of Padova, 35126 Padova, Italy
| | - Gian Paolo Rossi
- Nephrology and Hypertension Clinic, Department of Medicine, University of Padova, 35126 Padova, Italy
| | - Paul A Davis
- Department of Nutrition, University of California at Davis, Davis, CA 95616, USA
| | - Lorenzo A Calò
- Nephrology and Hypertension Clinic, Department of Medicine, University of Padova, 35126 Padova, Italy.
| |
Collapse
|
|
19
|
Lyu L, Wang H, Li B, Qin Q, Qi L, Nagarkatti M, Nagarkatti P, Janicki JS, Wang XL, Cui T. A critical role of cardiac fibroblast-derived exosomes in activating renin angiotensin system in cardiomyocytes. J Mol Cell Cardiol 2015; 89:268-79. [PMID: 26497614 DOI: 10.1016/j.yjmcc.2015.10.022] [Citation(s) in RCA: 165] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2015] [Revised: 10/10/2015] [Accepted: 10/19/2015] [Indexed: 01/26/2023]
Abstract
Chronic activation of the myocardial renin angiotensin system (RAS) elevates the local level of angiotensin II (Ang II) thereby inducing pathological cardiac hypertrophy, which contributes to heart failure. However, the precise underlying mechanisms have not been fully delineated. Herein we report a novel paracrine mechanism between cardiac fibroblasts (CF)s and cardiomyocytes whereby Ang II induces pathological cardiac hypertrophy. In cultured CFs, Ang II treatment enhanced exosome release via the activation of Ang II receptor types 1 (AT1R) and 2 (AT2R), whereas lipopolysaccharide, insulin, endothelin (ET)-1, transforming growth factor beta (TGFβ)1 or hydrogen peroxide did not. The CF-derived exosomes upregulated the expression of renin, angiotensinogen, AT1R, and AT2R, downregulated angiotensin-converting enzyme 2, and enhanced Ang II production in cultured cardiomyocytes. In addition, the CF exosome-induced cardiomyocyte hypertrophy was blocked by both AT1R and AT2R antagonists. Exosome inhibitors, GW4869 and dimethyl amiloride (DMA), inhibited CF-induced cardiomyocyte hypertrophy with little effect on Ang II-induced cardiomyocyte hypertrophy. Mechanistically, CF exosomes upregulated RAS in cardiomyocytes via the activation of mitogen-activated protein kinases (MAPKs) and Akt. Finally, Ang II-induced exosome release from cardiac fibroblasts and pathological cardiac hypertrophy were dramatically inhibited by GW4869 and DMA in mice. These findings demonstrate that Ang II stimulates CFs to release exosomes, which in turn increase Ang II production and its receptor expression in cardiomyocytes, thereby intensifying Ang II-induced pathological cardiac hypertrophy. Accordingly, specific targeting of Ang II-induced exosome release from CFs may serve as a novel therapeutic approach to treat cardiac pathological hypertrophy and heart failure.
Collapse
Affiliation(s)
- Linmao Lyu
- Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Hui Wang
- Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Bin Li
- Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Qingyun Qin
- Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Lei Qi
- Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Mitzi Nagarkatti
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29208, USA
| | - Prakash Nagarkatti
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29208, USA
| | - Joseph S Janicki
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208, USA
| | - Xing Li Wang
- Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China.
| | - Taixing Cui
- Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China; Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
| |
Collapse
|
|
20
|
Gopi V, Subramanian V, Manivasagam S, Vellaichamy E. Angiotensin II down-regulates natriuretic peptide receptor-A expression and guanylyl cyclase activity in H9c2 (2-1) cardiac myoblast cells: Role of ROS and NF-κB. Mol Cell Biochem 2015. [DOI: 10.1007/s11010-015-2513-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
|
|
21
|
Dai HL, Jia GZ, Zhao S. Total glycosides of Ranunculus japonius prevent hypertrophy in cardiomyocytes via alleviating chronic Ca(2+) overload. ACTA ACUST UNITED AC 2015; 30:37-43. [PMID: 25837359 DOI: 10.1016/s1001-9294(15)30007-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
OBJECTIVE To evaluate the in vitro anti-hypertrophic effect of total Glycosides of Ranunculus Japonius (TGRJ). METHODS Neonatal rat cardiomyocytes were cultured and hypertrophy was induced by administrating isoproterenol (ISO, 10 µmol/L) or angiotensin 2 (Ang 2, 1 µmol/L) for 48 hours. In the treatment groups, cells were pretreated with TGRJ (0.3 g/L) for 30 minutes prior to hypertrophic stimuli. The anti-hypertrophic effects of TGRJ were examined by measuring cell size, total protein content, and protein synthesis. Intracellular free Ca(2+) concentration ([Ca(2+)]i) was evaluated using fluorescence dye Fura-2/AM. Sacroplasmic/endoplasmic reticulum Ca(2+) ATPase 2a (SERCA2a), atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and beta-myosin heavy chain (β-MHC) protein expression levels were measured by Western blotting . SERCA2a activity was assayed by p-nitrophenal phosphate disodium salt hexahydrate method. RESULTS Increased cell size, total protein content, and protein synthesis following ISO or Ang 2 stimulation were significantly inhibited by pretreatment with TGRJ (all P<0.05). This anti-hypertrophic effect of TGRJ was confirmed by its suppressing effect on elevated expression of the three hypertrophic related genetic markers, ANP, BNP, and β-MHC. In addition, TGRJ inhibited ISO or Ang 2 induced up-regulation of [Ca(2+)]i under chronic but not acute conditions. And ISO or Ang 2 induced down-regulation of SERCA2a expression and activity was also effectively rectified by TGRJ pretreatment. CONCLUSIONS The results of present study suggested that TGRJ could prevent ISO or Ang 2 induced cardiac hypertrophy through improving chronic [Ca(2+)]i disorder, might via normalizing SERCA2a expression and activity.
Collapse
Affiliation(s)
- Hong-liang Dai
- Department of Community Health Nursing， Liaoning Medical University, Jinzhou, Liaoning 121001, China
| | - Gui-zhi Jia
- Department of Biochemistry and Molecular Biology, Liaoning Medical University, Jinzhou, Liaoning 121001, China
| | - Song Zhao
- Centre of Scientific Experiment, Liaoning Medical University, Jinzhou, Liaoning 121001, China
| |
Collapse
|
|
22
|
Small dedifferentiated cardiomyocytes bordering on microdomains of fibrosis: evidence for reverse remodeling with assisted recovery. J Cardiovasc Pharmacol 2015; 64:237-46. [PMID: 24785345 DOI: 10.1097/fjc.0000000000000111] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
With the perspective of functional myocardial regeneration, we investigated small cardiomyocytes bordering on microdomains of fibrosis, where they are dedifferentiated re-expressing fetal genes, and determined: (1) whether they are atrophied segments of the myofiber syncytium, (2) their redox state, (3) their anatomic relationship to activated myofibroblasts (myoFb), given their putative regulatory role in myocyte dedifferentiation and redifferentiation, (4) the relevance of proteolytic ligases of the ubiquitin-proteasome system as a mechanistic link to their size, and (5) whether they could be rescued from their dedifferentiated phenotype. Chronic aldosterone/salt treatment (ALDOST) was invoked, where hypertensive heart disease with attendant myocardial fibrosis creates the fibrillar collagen substrate for myocyte sequestration, with propensity for disuse atrophy, activated myoFb, and oxidative stress. To address phenotype rescue, 4 weeks of ALDOST was terminated followed by 4 weeks of neurohormonal withdrawal combined with a regimen of exogenous antioxidants, ZnSO4, and nebivolol (assisted recovery). Compared with controls, at 4 weeks of ALDOST, we found small myocytes to be: (1) sequestered by collagen fibrils emanating from microdomains of fibrosis and representing atrophic segments of the myofiber syncytia, (2) dedifferentiated re-expressing fetal genes (β-myosin heavy chain and atrial natriuretic peptide), (3) proximal to activated myoFb expressing α-smooth muscle actin microfilaments and angiotensin-converting enzyme, (4) expressing reactive oxygen species and nitric oxide with increased tissue 8-isoprostane, coupled to ventricular diastolic and systolic dysfunction, and (5) associated with upregulated redox-sensitive proteolytic ligases MuRF1 and atrogin-1. In a separate study, we did not find evidence of myocyte replication (BrdU labeling) or expression of stem cell antigen (c-Kit) at weeks 1-4 ALDOST. Assisted recovery caused complete disappearance of myoFb from sites of fibrosis with redifferentiation of these myocytes, loss of oxidative stress, and ubiquitin-proteasome system activation, with restoration of nitric oxide and improved ventricular function. Thus, small dedifferentiated myocytes bordering on microdomains of fibrosis can re-differentiate and represent a potential source of autologous cells for functional myocardial regeneration.
Collapse
|
|
23
|
Lee S, Paudel O, Jiang Y, Yang XR, Sham JSK. CD38 mediates angiotensin II-induced intracellular Ca(2+) release in rat pulmonary arterial smooth muscle cells. Am J Respir Cell Mol Biol 2015; 52:332-41. [PMID: 25078456 DOI: 10.1165/rcmb.2014-0141oc] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
CD38 is a multifunctional enzyme that catalyzes the formation of the endogenous Ca(2+)-mobilizing messengers cyclic ADP-ribose (cADPR) and nicotinic acid adenosine dinucleotide phosphate (NAADP) for the activation of ryanodine receptors (RyRs) of sarcoplasmic reticulum and NAADP-sensitive Ca(2+) release channels in endolysosomes, respectively. It plays important roles in systemic vascular functions, but there is little information on CD38 in pulmonary arterial smooth muscle cells (PASMCs). Earlier studies suggested a redox-sensing role of CD38 in hypoxic pulmonary vasoconstriction. This study sought to characterize its roles in angiotensin II (Ang II)-induced Ca(2+) release (AICR) in PASMCs. Examination of CD38 expression in various rat arteries found high levels of CD38 mRNA and protein in pulmonary arteries. The Ang II-elicited Ca(2+) response consisted of extracellular Ca(2+) influx and intracellular Ca(2+) release in PASMCs. AICR activated in the absence of extracellular Ca(2+) was reduced by pharmacological or siRNA inhibition of CD38, by the cADPR antagonist 8-bromo-cADPR or ryanodine, and by the NAADP antagonist Ned-19 or disruption of endolysosomal Ca(2+) stores with the vacuolar H(+)-ATPase inhibitor bafilomycin A1. Suppression of AICR by the inhibitions of cADPR- and NAADP-dependent pathways were nonadditive, indicating interdependence of RyR- and NAADP-gated Ca(2+) release. Furthermore, AICR was inhibited by the protein kinase C inhibitor staurosporine, the nonspecific NADPH oxidase (NOX) inhibitors apocynin and diphenyleneiodonium, the NOX2-specific inhibitor gp91ds-tat, and the scavenger of reactive oxygen species (ROS) tempol. These results provide the first evidence that Ang II activates CD38-dependent Ca(2+) release via the NOX2-ROS pathway in PASMCs.
Collapse
Affiliation(s)
- Suengwon Lee
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | | | | | | | | |
Collapse
|
|
24
|
Ca²⁺ signal-induced cardiomyocyte hypertrophy through activation of myocardin. Gene 2014; 557:43-51. [PMID: 25485719 DOI: 10.1016/j.gene.2014.12.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Revised: 11/21/2014] [Accepted: 12/03/2014] [Indexed: 11/21/2022]
Abstract
Hypertrophic growth of cardiomyocytes in response to pressure overload is an important stage during the development of many cardiac diseases. Ca(2+) overload as well as subsequent activation of Ca(2+) signaling pathways has been reported to induce cardiac hypertrophy. Myocardin, a transcription cofactor of serum response factor (SRF), is a key transducer of hypertrophic signals. However, the direct role of myocardin in Ca(2+) signal-induced cardiomyocyte hypertrophy has not been explained clearly. In the present study, we discovered that embryonic rat heart-derived H9c2 cells responded to the stimulation of calcium ionophore A23187 with a cell surface area enlargement and an increased expression of cardiac hypertrophy marker genes. Increased Ca(2+) also induces an organization of sarcomeres in neonatal rat cardiomyocytes, as revealed by α-actinin staining. Increased Ca(2+) could upregulate the expression of myocardin. Knockdown of myocardin by shRNA attenuates hypertrophic responses triggered by increased intracellular Ca(2+), suggesting that Ca(2+) signals induce cardiomyocyte hypertrophy partly through activation of myocardin. Furthermore, A23187 treatment directly activates myocardin promoter, chelation of Ca(2+) by EGTA inhibits this activation and knockdown of myocardin expression using shRNA also abrogates A23187-induced ANF and SK-α-actin promoter activity. CSA (calcineurin inhibitor) and KN93 (CaMKII inhibitor) inhibit A23187-induced the increase in myocardin expression. These results suggest that myocardin plays a critical role in Ca(2+) signal-induced cardiomyocyte hypertrophy, which may serve as a novel mechanism that is important for cardiac hypertrophy.
Collapse
|
|
25
|
Ko E, Choi H, Kim B, Kim M, Park KN, Bae IH, Sung YK, Lee TR, Shin DW, Bae YS. Testosterone stimulates Duox1 activity through GPRC6A in skin keratinocytes. J Biol Chem 2014; 289:28835-45. [PMID: 25164816 DOI: 10.1074/jbc.m114.583450] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Testosterone is an endocrine hormone with functions in reproductive organs, anabolic events, and skin homeostasis. We report here that GPRC6A serves as a sensor and mediator of the rapid action of testosterone in epidermal keratinocytes. The silencing of GPRC6A inhibited testosterone-induced intracellular calcium ([Ca(2+)]i) mobilization and H2O2 generation. These results indicated that a testosterone-GPRC6A complex is required for activation of Gq protein, IP3 generation, and [Ca(2+)]i mobilization, leading to Duox1 activation. H2O2 generation by testosterone stimulated the apoptosis of keratinocytes through the activation of caspase-3. The application of testosterone into three-dimensional skin equivalents increased the apoptosis of keratinocytes between the granular and stratified corneum layers. These results support an understanding of the molecular mechanism of testosterone-dependent apoptosis in which testosterone stimulates H2O2 generation through the activation of Duox1.
Collapse
Affiliation(s)
- Eunbi Ko
- From the Department of Life Science and GT5 program, Ewha Womans University
| | - Hyun Choi
- Bioscience Research Institute, Amorepacific Corporation R&D Center, Yongin-si, Gyeonggi-do, 446-729 and
| | - Borim Kim
- From the Department of Life Science and GT5 program, Ewha Womans University
| | - Minsun Kim
- From the Department of Life Science and GT5 program, Ewha Womans University
| | - Kkot-Nara Park
- From the Department of Life Science and GT5 program, Ewha Womans University
| | - Il-Hong Bae
- Bioscience Research Institute, Amorepacific Corporation R&D Center, Yongin-si, Gyeonggi-do, 446-729 and
| | - Young Kwan Sung
- the Department of Immunology, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea
| | - Tae Ryong Lee
- Bioscience Research Institute, Amorepacific Corporation R&D Center, Yongin-si, Gyeonggi-do, 446-729 and
| | - Dong Wook Shin
- Bioscience Research Institute, Amorepacific Corporation R&D Center, Yongin-si, Gyeonggi-do, 446-729 and
| | - Yun Soo Bae
- From the Department of Life Science and GT5 program, Ewha Womans University,
| |
Collapse
|
|
26
|
The Renin-Angiotensin-aldosterone system in vascular inflammation and remodeling. Int J Inflam 2014; 2014:689360. [PMID: 24804145 PMCID: PMC3997861 DOI: 10.1155/2014/689360] [Citation(s) in RCA: 225] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Revised: 02/28/2014] [Accepted: 03/03/2014] [Indexed: 12/31/2022] Open
Abstract
The RAAS through its physiological effectors plays a key role in promoting and maintaining inflammation. Inflammation is an important mechanism in the development and progression of CVD such as hypertension and atherosclerosis. In addition to its main role in regulating blood pressure and its role in hypertension, RAAS has proinflammatory and profibrotic effects at cellular and molecular levels. Blocking RAAS provides beneficial effects for the treatment of cardiovascular and renal diseases. Evidence shows that inhibition of RAAS positively influences vascular remodeling thus improving CVD outcomes. The beneficial vascular effects of RAAS inhibition are likely due to decreasing vascular inflammation, oxidative stress, endothelial dysfunction, and positive effects on regeneration of endothelial progenitor cells. Inflammatory factors such as ICAM-1, VCAM-1, TNFα, IL-6, and CRP have key roles in mediating vascular inflammation and blocking RAAS negatively modulates the levels of these inflammatory molecules. Some of these inflammatory markers are clinically associated with CVD events. More studies are required to establish long-term effects of RAAS inhibition on vascular inflammation, vascular cells regeneration, and CVD clinical outcomes. This review presents important information on RAAS's role on vascular inflammation, vascular cells responses to RAAS, and inhibition of RAAS signaling in the context of vascular inflammation, vascular remodeling, and vascular inflammation-associated CVD. Nevertheless, the review also equates the need to rethink and rediscover new RAAS inhibitors.
Collapse
|
|
27
|
Wei W, Graeff R, Yue J. Roles and mechanisms of the CD38/cyclic adenosine diphosphate ribose/Ca 2+ signaling pathway. World J Biol Chem 2014; 5:58-67. [PMID: 24600514 PMCID: PMC3942542 DOI: 10.4331/wjbc.v5.i1.58] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Revised: 11/09/2013] [Accepted: 12/19/2013] [Indexed: 02/05/2023] Open
Abstract
Mobilization of intracellular Ca2+ stores is involved in many diverse cell functions, including: cell proliferation; differentiation; fertilization; muscle contraction; secretion of neurotransmitters, hormones and enzymes; and lymphocyte activation and proliferation. Cyclic adenosine diphosphate ribose (cADPR) is an endogenous Ca2+ mobilizing nucleotide present in many cell types and species, from plants to animals. cADPR is formed by ADP-ribosyl cyclases from nicotinamide adenine dinucleotide. The main ADP-ribosyl cyclase in mammals is CD38, a multi-functional enzyme and a type II membrane protein. It has been shown that many extracellular stimuli can induce cADPR production that leads to calcium release or influx, establishing cADPR as a second messenger. cADPR has been linked to a wide variety of cellular processes, but the molecular mechanisms regarding cADPR signaling remain elusive. The aim of this review is to summarize the CD38/cADPR/Ca2+ signaling pathway, focusing on the recent advances involving the mechanism and physiological functions of cADPR-mediated Ca2+ mobilization.
Collapse
|
|
28
|
De Giusti VC, Caldiz CI, Ennis IL, Pérez NG, Cingolani HE, Aiello EA. Mitochondrial reactive oxygen species (ROS) as signaling molecules of intracellular pathways triggered by the cardiac renin-angiotensin II-aldosterone system (RAAS). Front Physiol 2013; 4:126. [PMID: 23755021 PMCID: PMC3667248 DOI: 10.3389/fphys.2013.00126] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2013] [Accepted: 05/13/2013] [Indexed: 12/22/2022] Open
Abstract
Mitochondria represent major sources of basal reactive oxygen species (ROS) production of the cardiomyocyte. The role of ROS as signaling molecules that mediate different intracellular pathways has gained increasing interest among physiologists in the last years. In our lab, we have been studying the participation of mitochondrial ROS in the intracellular pathways triggered by the renin-angiotensin II-aldosterone system (RAAS) in the myocardium during the past few years. We have demonstrated that acute activation of cardiac RAAS induces mitochondrial ATP-dependent potassium channel (mitoKATP) opening with the consequent enhanced production of mitochondrial ROS. These oxidant molecules, in turn, activate membrane transporters, as sodium/hydrogen exchanger (NHE-1) and sodium/bicarbonate cotransporter (NBC) via the stimulation of the ROS-sensitive MAPK cascade. The stimulation of such effectors leads to an increase in cardiac contractility. In addition, it is feasible to suggest that a sustained enhanced production of mitochondrial ROS induced by chronic cardiac RAAS, and hence, chronic NHE-1 and NBC stimulation, would also result in the development of cardiac hypertrophy.
Collapse
Affiliation(s)
- V C De Giusti
- Facultad de Ciencias Médicas, Centro de Investigaciones Cardiovasculares, UNLP-CONICET La Plata, Argentina
| | | | | | | | | | | |
Collapse
|
|
29
|
Zhang H, Gomez AM, Wang X, Yan Y, Zheng M, Cheng H. ROS regulation of microdomain Ca(2+) signalling at the dyads. Cardiovasc Res 2013; 98:248-58. [PMID: 23455546 DOI: 10.1093/cvr/cvt050] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Reactive oxygen species (ROS) are emerging as centre-stage players in cardiac functional regulation. ROS and Ca(2+) signals converge at dyads, the structural and functional units of cardiac excitation-contraction coupling. These two prominent signalling systems are intertwined with ROS modulation of the entire Ca(2+)-signalling network, and vice versa. While constitutively generated homoeostatic ROS are important in setting the redox potential of the intracellular milieu, dynamic signalling ROS shape microdomain and global Ca(2+) signals on both the beat-to-beat and greater time scales. However, ROS effects are complex and subtle, characterized by multiphasic and bidirectional Ca(2+) responses; and sustained oxidative stress may lead to compromised contractility and arrhythmogenicity. These new understandings should be leveraged to harness ROS for their beneficial roles while avoiding deleterious effects in the heart.
Collapse
Affiliation(s)
- Huiliang Zhang
- State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, Peking University, Beijing 100871, China
| | | | | | | | | | | |
Collapse
|
|
30
|
Kono R, Okuno Y, Nakamura M, Inada KI, Tokuda A, Yamashita M, Hidaka R, Utsunomiya H. Peach (Prunus persica) extract inhibits angiotensin II-induced signal transduction in vascular smooth muscle cells. Food Chem 2013; 139:371-6. [PMID: 23561119 DOI: 10.1016/j.foodchem.2013.02.019] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2012] [Revised: 01/28/2013] [Accepted: 02/05/2013] [Indexed: 10/27/2022]
Abstract
Angiotensin II (Ang II) is a vasoactive hormone that has been implicated in cardiovascular diseases. Here, the effect of peach, Prunus persica L. Batsch, pulp extract on Ang II-induced intracellular Ca(2+) mobilization, reactive oxygen species (ROS) production and signal transduction events in cultured vascular smooth muscle cells (VSMCs) was investigated. Pretreatment of peach ethyl acetate extract inhibited Ang II-induced intracellular Ca(2+) elevation in VSMCs. Furthermore, Ang II-induced ROS generation, essential for signal transduction events, was diminished by the peach ethyl acetate extract. The peach ethyl acetate extract also attenuated the Ang II-induced phosphorylation of epidermal growth factor receptor and myosin phosphatase target subunit 1, both of which are associated with atherosclerosis and hypertension. These results suggest that peach ethyl acetate extract may have clinical potential for preventing cardiovascular diseases by interfering with Ang II-induced intracellular Ca(2+) elevation, the generation of ROS, and then blocking signal transduction events.
Collapse
Affiliation(s)
- Ryohei Kono
- Department of Strategic Surveillance for Functional Food and Comprehensive Traditional Medicine, Wakayama Medical University, Kimiidera 811-1, Wakayama City, Wakayama 641-0012, Japan.
| | | | | | | | | | | | | | | |
Collapse
|
|
31
|
Kyrychenko S, Poláková E, Kang C, Pocsai K, Ullrich ND, Niggli E, Shirokova N. Hierarchical accumulation of RyR post-translational modifications drives disease progression in dystrophic cardiomyopathy. Cardiovasc Res 2012; 97:666-75. [PMID: 23263329 DOI: 10.1093/cvr/cvs425] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
AIMS Duchenne muscular dystrophy (DMD) is a muscle disease with serious cardiac complications. Changes in Ca(2+) homeostasis and oxidative stress were recently associated with cardiac deterioration, but the cellular pathophysiological mechanisms remain elusive. We investigated whether the activity of ryanodine receptor (RyR) Ca(2+) release channels is affected, whether changes in function are cause or consequence and which post-translational modifications drive disease progression. METHODS AND RESULTS Electrophysiological, imaging, and biochemical techniques were used to study RyRs in cardiomyocytes from mdx mice, an animal model of DMD. Young mdx mice show no changes in cardiac performance, but do so after ∼8 months. Nevertheless, myocytes from mdx pups exhibited exaggerated Ca(2+) responses to mechanical stress and 'hypersensitive' excitation-contraction coupling, hallmarks of increased RyR Ca(2+) sensitivity. Both were normalized by antioxidants, inhibitors of NAD(P)H oxidase and CaMKII, but not by NO synthases and PKA antagonists. Sarcoplasmic reticulum Ca(2+) load and leak were unchanged in young mdx mice. However, by the age of 4-5 months and in senescence, leak was increased and load was reduced, indicating disease progression. By this age, all pharmacological interventions listed above normalized Ca(2+) signals and corrected changes in ECC, Ca(2+) load, and leak. CONCLUSION Our findings suggest that increased RyR Ca(2+) sensitivity precedes and presumably drives the progression of dystrophic cardiomyopathy, with oxidative stress initiating its development. RyR oxidation followed by phosphorylation, first by CaMKII and later by PKA, synergistically contributes to cardiac deterioration.
Collapse
Affiliation(s)
- Sergii Kyrychenko
- Department of Pharmacology and Physiology, New Jersey Medical School, 185 S. Orange Ave., Newark, NJ 07103, USA
| | | | | | | | | | | | | |
Collapse
|
|
32
|
Shirokova N, Niggli E. Cardiac phenotype of Duchenne Muscular Dystrophy: insights from cellular studies. J Mol Cell Cardiol 2012; 58:217-24. [PMID: 23261966 DOI: 10.1016/j.yjmcc.2012.12.009] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2012] [Revised: 11/07/2012] [Accepted: 12/11/2012] [Indexed: 12/11/2022]
Abstract
Dilated cardiomyopathy is a serious and almost inevitable complication of Duchenne Muscular Dystrophy, a devastating and fatal disease of skeletal muscle resulting from the lack of functional dystrophin, a protein linking the cytoskeleton to the extracellular matrix. Ultimately, it leads to congestive heart failure and arrhythmias resulting from both cardiac muscle fibrosis and impaired function of the remaining cardiomyocytes. Here we summarize findings obtained in several laboratories, focusing on cellular mechanisms that result in degradation of cardiac functions in dystrophy.
Collapse
Affiliation(s)
- Natalia Shirokova
- Department of Pharmacology and Physiology, University of Medicine and Dentistry - NJMS, Newark, NJ 07103, USA.
| | | |
Collapse
|
|
33
|
Abstract
Redox signaling refers to the specific and usually reversible oxidation/reduction modification of molecules involved in cellular signaling pathways. In the heart, redox signaling regulates several physiological processes (eg, excitation-contraction coupling) and is involved in a wide variety of pathophysiological and homoeostatic or stress response pathways. Reactive oxygen species involved in cardiac redox signaling may derive from many sources, but NADPH oxidases, as dedicated sources of signaling reactive oxygen species, seem to be especially important. An increasing number of specific posttranslational oxidative modifications involved in cardiac redox signaling are being defined, along with the reactive oxygen species sources that are involved. Here, we review current knowledge on the molecular targets of signaling reactive oxygen species in cardiac cells and their involvement in cardiac physiopathology. Advances in this field may allow the development of targeted therapeutic strategies for conditions such as heart failure as opposed to the general antioxidant approaches that have failed to date.
Collapse
|