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1
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Lindsay RT, Thisted L, Zois NE, Thrane ST, West JA, Fosgerau K, Griffin JL, Fink LN, Murray AJ. Beta-adrenergic agonism protects mitochondrial metabolism in the pancreatectomised rat heart. Sci Rep 2024; 14:19383. [PMID: 39169098 PMCID: PMC11339431 DOI: 10.1038/s41598-024-70335-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 08/14/2024] [Indexed: 08/23/2024] Open
Abstract
The diabetic heart is characterised by functional, morphological and metabolic alterations predisposing it to contractile failure. Chronic sympathetic activation is a feature of the pathogenesis of heart failure, however the type 1 diabetic heart shows desensitisation to β-adrenergic stimulation. Here, we sought to understand the impact of repeated isoprenaline-mediated β-stimulation upon cardiac mitochondrial respiratory capacity and substrate metabolism in the 90% pancreatectomy (Px) rat model of type 1 diabetes. We hypothesised these hearts would be relatively protected against the metabolic impact of stress-induced cardiomyopathy. We found that individually both Px and isoprenaline suppressed cardiac mitochondrial respiration, but that this was preserved in Px rats receiving isoprenaline. Px and isoprenaline had contrasting effects on cardiac substrate metabolism, with increased reliance upon cardiac fatty acid oxidation capacity and altered ketone metabolism in the hearts of Px rats, but enhanced capacity for glucose uptake and metabolism in isoprenaline-treated rats. Moreover, Px rats were protected against isoprenaline-induced mortality, whilst isoprenaline elevated cGMP and protected myocardial energetic status in Px rat hearts. Our work suggests that adrenergic stimulation may be protective in the type 1 diabetic heart, and underlines the importance of studying pathological features in combination when modeling complex disease in rodents.
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Affiliation(s)
- Ross T Lindsay
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
- Gubra A/S, Hørsholm Kongevej 11B, 2970, Hørsholm, Denmark.
- Department of Biochemistry and Systems Biology Centre, University of Cambridge, Cambridge, UK.
| | - Louise Thisted
- Gubra A/S, Hørsholm Kongevej 11B, 2970, Hørsholm, Denmark
| | - Nora E Zois
- Gubra A/S, Hørsholm Kongevej 11B, 2970, Hørsholm, Denmark
- Ascendis Pharma A/S, Hellerup, Denmark
| | | | - James A West
- Department of Biochemistry and Systems Biology Centre, University of Cambridge, Cambridge, UK
- AstraZeneca, Cambridge, UK
| | - Keld Fosgerau
- Gubra A/S, Hørsholm Kongevej 11B, 2970, Hørsholm, Denmark
- Pephexia Therapeutics ApS, Copenhagen, Denmark
| | - Julian L Griffin
- Department of Biochemistry and Systems Biology Centre, University of Cambridge, Cambridge, UK
- The Rowett Institute, University of Aberdeen, Aberdeen, UK
| | - Lisbeth N Fink
- Gubra A/S, Hørsholm Kongevej 11B, 2970, Hørsholm, Denmark
- Ferring Pharmaceuticals A/S, Kastrup, Denmark
| | - Andrew J Murray
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
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2
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Jankauskas SS, Kansakar U, Varzideh F, Wilson S, Mone P, Lombardi A, Gambardella J, Santulli G. Heart failure in diabetes. Metabolism 2021; 125:154910. [PMID: 34627874 PMCID: PMC8941799 DOI: 10.1016/j.metabol.2021.154910] [Citation(s) in RCA: 131] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 10/02/2021] [Accepted: 10/04/2021] [Indexed: 12/16/2022]
Abstract
Heart failure and cardiovascular disorders represent the leading cause of death in diabetic patients. Here we present a systematic review of the main mechanisms underlying the development of diabetic cardiomyopathy. We also provide an excursus on the relative contribution of cardiomyocytes, fibroblasts, endothelial and smooth muscle cells to the pathophysiology of heart failure in diabetes. After having described the preclinical tools currently available to dissect the mechanisms of this complex disease, we conclude with a section on the most recent updates of the literature on clinical management.
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Affiliation(s)
- Stanislovas S Jankauskas
- Department of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, New York, NY 10461, USA; Department of Molecular Pharmacology, Einstein Institute for Neuroimmunology and Inflammation, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Urna Kansakar
- Department of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, New York, NY 10461, USA; Department of Molecular Pharmacology, Einstein Institute for Neuroimmunology and Inflammation, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Fahimeh Varzideh
- Department of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, New York, NY 10461, USA; Department of Molecular Pharmacology, Einstein Institute for Neuroimmunology and Inflammation, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Scott Wilson
- Department of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Pasquale Mone
- Department of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Angela Lombardi
- Department of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Jessica Gambardella
- Department of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, New York, NY 10461, USA; Department of Molecular Pharmacology, Einstein Institute for Neuroimmunology and Inflammation, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA; International Translational Research and Medical Education (ITME), Department of Advanced Biomedical Science, "Federico II" University, 80131 Naples, Italy
| | - Gaetano Santulli
- Department of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, New York, NY 10461, USA; Department of Molecular Pharmacology, Einstein Institute for Neuroimmunology and Inflammation, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA; International Translational Research and Medical Education (ITME), Department of Advanced Biomedical Science, "Federico II" University, 80131 Naples, Italy.
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3
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Gaitán-González P, Sánchez-Hernández R, Arias-Montaño JA, Rueda A. Tale of two kinases: Protein kinase A and Ca 2+/calmodulin-dependent protein kinase II in pre-diabetic cardiomyopathy. World J Diabetes 2021; 12:1704-1718. [PMID: 34754372 PMCID: PMC8554373 DOI: 10.4239/wjd.v12.i10.1704] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 07/28/2021] [Accepted: 08/30/2021] [Indexed: 02/06/2023] Open
Abstract
Metabolic syndrome is a pre-diabetic state characterized by several biochemical and physiological alterations, including insulin resistance, visceral fat accumulation, and dyslipidemias, which increase the risk for developing cardiovascular disease. Metabolic syndrome is associated with augmented sympathetic tone, which could account for the etiology of pre-diabetic cardiomyopathy. This review summarizes the current knowledge of the pathophysiological consequences of enhanced and sustained β-adrenergic response in pre-diabetes, focusing on cardiac dysfunction reported in diet-induced experimental models of pre-diabetic cardiomyopathy. The research reviewed indicates that both protein kinase A and Ca2+/calmodulin-dependent protein kinase II play important roles in functional responses mediated by β1-adrenoceptors; therefore, alterations in the expression or function of these kinases can be deleterious. This review also outlines recent information on the role of protein kinase A and Ca2+/calmodulin-dependent protein kinase II in abnormal Ca2+ handling by cardiomyocytes from diet-induced models of pre-diabetic cardiomyopathy.
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Affiliation(s)
- Pamela Gaitán-González
- Department of Biochemistry, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México 07360, Mexico
| | - Rommel Sánchez-Hernández
- Department of Physiology, Biophysics and Neurosciences, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México 07360, Mexico
| | - José-Antonio Arias-Montaño
- Department of Physiology, Biophysics and Neurosciences, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México 07360, Mexico
| | - Angélica Rueda
- Department of Biochemistry, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México 07360, Mexico
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4
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Hanna R, Nour-Eldine W, Saliba Y, Dagher-Hamalian C, Hachem P, Abou-Khalil P, Mika D, Varin A, El Hayek MS, Pereira L, Farès N, Vandecasteele G, Abi-Gerges A. Cardiac Phosphodiesterases Are Differentially Increased in Diabetic Cardiomyopathy. Life Sci 2021; 283:119857. [PMID: 34339715 DOI: 10.1016/j.lfs.2021.119857] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 07/19/2021] [Accepted: 07/20/2021] [Indexed: 12/29/2022]
Abstract
AIM Diabetic cardiomyopathy (DCM) accomodates a spectrum of cardiac abnormalities. This study aims to investigate whether DCM is associated with changes in cyclic adenosine 3'-5' monophosphate (cAMP) signaling, particularly cyclic nucleotide phosphodiesterases (PDEs). MAIN METHODS Type 1 diabetes (T1D) was induced in rats by streptozotocin (STZ, 65 mg/kg) injection. Myocardial remodeling, structure and function were evaluated by histology and echocardiography, respectively. We delineated the sequential changes affecting cAMP signaling and characterized the expression pattern of the predominant cardiac PDE isoforms (PDE 1-5) and β-adrenergic (β-AR) receptors at 4, 8 and 12 weeks following diabetes induction, by real-time quantitative PCR and Western blot. cAMP levels were measured by immunoassays. KEY FINDINGS T1D-induced DCM was associated with cardiac remodeling, steatosis and fibrosis. Upregulation of β1-AR receptor transcripts was noted in diabetic hearts at 4 weeks along with an increase in cAMP levels and an upregulation in the ejection fraction and fraction shortening. However, β2-AR receptors expression remained unchanged regardless of the disease stage. Moreover, we noted an early and specific upregulation of cardiac PDE1A, PDE2A, PDE4B, PDE4D and PDE5A expression at week 4, followed by increases in PDE3A levels in diabetic hearts at week 8. However, DCM was not associated with changes in PDE4A gene expression irrespective of the disease stage. SIGNIFICANCE We show for the first time differential and time-specific regulations in cardiac PDEs, data that may prove useful in proposing new therapeutic approaches in T1D-induced DCM.
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Affiliation(s)
- Rita Hanna
- Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, P.O. Box 36, Byblos, Lebanon
| | - Wared Nour-Eldine
- Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, P.O. Box 36, Byblos, Lebanon
| | - Youakim Saliba
- Faculté de Médecine, Laboratoire de Recherche en Physiologie et Physiopathologie, LRPP, Pôle Technologie Santé, Université Saint Joseph, Beirut, Lebanon
| | - Carole Dagher-Hamalian
- Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, P.O. Box 36, Byblos, Lebanon
| | - Pia Hachem
- Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, P.O. Box 36, Byblos, Lebanon
| | - Pamela Abou-Khalil
- Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, P.O. Box 36, Byblos, Lebanon
| | - Delphine Mika
- Signaling and Cardiovascular Pathophysiology, UMR-S1180, Université Paris-Saclay, 92296 Châtenay-Malabry, France
| | - Audrey Varin
- Signaling and Cardiovascular Pathophysiology, UMR-S1180, Université Paris-Saclay, 92296 Châtenay-Malabry, France
| | - Magali Samia El Hayek
- Signaling and Cardiovascular Pathophysiology, UMR-S1180, Université Paris-Saclay, 92296 Châtenay-Malabry, France
| | - Laëtitia Pereira
- Signaling and Cardiovascular Pathophysiology, UMR-S1180, Université Paris-Saclay, 92296 Châtenay-Malabry, France
| | - Nassim Farès
- Faculté de Médecine, Laboratoire de Recherche en Physiologie et Physiopathologie, LRPP, Pôle Technologie Santé, Université Saint Joseph, Beirut, Lebanon
| | - Grégoire Vandecasteele
- Signaling and Cardiovascular Pathophysiology, UMR-S1180, Université Paris-Saclay, 92296 Châtenay-Malabry, France
| | - Aniella Abi-Gerges
- Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, P.O. Box 36, Byblos, Lebanon.
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Erdogan BR, Michel MC, Arioglu-Inan E. Expression and Signaling of β-Adrenoceptor Subtypes in the Diabetic Heart. Cells 2020; 9:cells9122548. [PMID: 33256212 PMCID: PMC7759850 DOI: 10.3390/cells9122548] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 11/20/2020] [Accepted: 11/24/2020] [Indexed: 12/18/2022] Open
Abstract
Diabetes is a chronic, endocrine disorder that effects millions of people worldwide. Cardiovascular complications are the major cause of diabetes-related morbidity and mortality. Cardiac β1- and β2-adrenoceptor (AR) stimulation mediates positive inotropy and chronotropy, whereas β3-AR mediates negative inotropic effect. Changes in β-AR responsiveness are thought to be an important factor that contributes to the diabetic cardiac dysfunction. Diabetes related changes in β-AR expression, signaling, and β-AR mediated cardiac function have been studied by several investigators for many years. In the present review, we have screened PubMed database to obtain relevant articles on this topic. Our search has ended up with wide range of different findings about the effect of diabetes on β-AR mediated changes both in molecular and functional level. Considering these inconsistent findings, the effect of diabetes on cardiac β-AR still remains to be clarified.
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Affiliation(s)
- Betul R. Erdogan
- Department of Pharmacology, Faculty of Pharmacy, Ankara University, 06560 Ankara, Turkey;
- Department of Pharmacology, Faculty of Pharmacy, Izmir Katip Celebi University, 35620 Izmir, Turkey
| | - Martin C. Michel
- Department of Pharmacology, Johannes Gutenberg University, 55131 Mainz, Germany;
| | - Ebru Arioglu-Inan
- Department of Pharmacology, Faculty of Pharmacy, Ankara University, 06560 Ankara, Turkey;
- Correspondence:
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6
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Carillion A, Feldman S, Na N, Biais M, Carpentier W, Birenbaum A, Cagnard N, Loyer X, Bonnefont-Rousselot D, Hatem S, Riou B, Amour J. Atorvastatin reduces β-Adrenergic dysfunction in rats with diabetic cardiomyopathy. PLoS One 2017; 12:e0180103. [PMID: 28727746 PMCID: PMC5519044 DOI: 10.1371/journal.pone.0180103] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 06/09/2017] [Indexed: 12/12/2022] Open
Abstract
Background In the diabetic heart the β-adrenergic response is altered partly by down-regulation of the β1-adrenoceptor, reducing its positive inotropic effect and up-regulation of the β3-adrenoceptor, increasing its negative inotropic effect. Statins have clinical benefits on morbidity and mortality in diabetic patients which are attributed to their “pleiotropic” effects. The objective of our study was to investigate the role of statin treatment on β-adrenergic dysfunction in diabetic rat cardiomyocytes. Methods β-adrenergic responses were investigated in vivo (echocardiography) and ex vivo (left ventricular papillary muscles) in healthy and streptozotocin-induced diabetic rats, who were pre-treated or not by oral atorvastatin over 15 days (50 mg.kg-1.day-1). Micro-array analysis and immunoblotting were performed in left ventricular homogenates. Data are presented as mean percentage of baseline ± SD. Results Atorvastatin restored the impaired positive inotropic effect of β-adrenergic stimulation in diabetic hearts compared with healthy hearts both in vivo and ex vivo but did not suppress the diastolic dysfunction of diabetes. Atorvastatin changed the RNA expression of 9 genes in the β-adrenergic pathway and corrected the protein expression of β1-adrenoceptor and β1/β3-adrenoceptor ratio, and multidrug resistance protein 4 (MRP4). Nitric oxide synthase (NOS) inhibition abolished the beneficial effects of atorvastatin on the β-adrenoceptor response. Conclusions Atorvastatin restored the positive inotropic effect of the β-adrenoceptor stimulation in diabetic cardiomyopathy. This effect is mediated by multiple modifications in expression of proteins in the β-adrenergic signaling pathway, particularly through the NOS pathway.
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Affiliation(s)
- Aude Carillion
- Sorbonne Universités, UPMC Univ Paris 06, UMR INSERM 1166, IHU ICAN, and Department of Anesthesiology and Critical Care Medicine, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France
| | - Sarah Feldman
- Sorbonne Universités, UPMC Univ Paris 06, UMR INSERM 1166, IHU ICAN, and Department of Anesthesiology and Critical Care Medicine, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France
| | - Na Na
- Sorbonne Universités, UPMC Univ Paris 06, UMR INSERM 1166, IHU ICAN, and Department of Emergency Medicine and Surgery, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France
| | - Matthieu Biais
- Sorbonne Universités, UPMC Univ Paris 06, UMR INSERM 1166, IHU ICAN, and Department of Anesthesiology and Critical Care, Université Bordeaux Segalen, Hôpital Pellegrin, Bordeaux, France
| | - Wassila Carpentier
- Sorbonne Universités, UPMC Univ Paris 06, Post-Genomic Platform, Paris, France
| | - Aurélie Birenbaum
- Sorbonne Universités, UPMC Univ Paris 06, UMR INSERM 1166, IHU ICAN, and Department of Anesthesiology and Critical Care Medicine, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France
| | - Nicolas Cagnard
- Sorbonne Universités, Université Paris Descartes, Bioinformatics Platform, Paris, France
| | - Xavier Loyer
- Sorbonne Universités, Université Paris Descartes, UMRS INSERM U970, Cardiovascular Research center, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France
| | - Dominique Bonnefont-Rousselot
- Sorbonne Paris Cité, Paris Descartes University, CNRS UMR8258—INSERM U1022, Faculty of Pharmacy, Department of Metabolic Biochemistry, La Pitié Salpêtrière-Charles Foix University Hospital (AP-HP), Paris, France
| | - Stéphane Hatem
- Sorbonne Universités, UPMC Univ Paris 06, UMR INSERM 1166, IHU ICAN, Sorbonne Universités, UPMC Univ Paris 06, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France
| | - Bruno Riou
- Sorbonne Universités, UPMC Univ Paris 06, UMR INSERM 1166, IHU ICAN, and Department of Emergency Medicine and Surgery, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France
| | - Julien Amour
- Sorbonne Universités, UPMC Univ Paris 06, UMR INSERM 1166, IHU ICAN, and Department of Anesthesiology and Critical Care Medicine, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France
- * E-mail:
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Dhalla NS, Takeda N, Rodriguez-Leyva D, Elimban V. Mechanisms of subcellular remodeling in heart failure due to diabetes. Heart Fail Rev 2014; 19:87-99. [PMID: 23436108 DOI: 10.1007/s10741-013-9385-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Diabetic cardiomyopathy is not only associated with heart failure but there also occurs a loss of the positive inotropic effect of different agents. It is now becoming clear that cardiac dysfunction in chronic diabetes is intimately involved with Ca(2+)-handling abnormalities, metabolic defects and impaired sensitivity of myofibrils to Ca(2+) in cardiomyocytes. On the other hand, loss of the inotropic effect in diabetic myocardium is elicited by changes in signal transduction mechanisms involving hormone receptors and depressions in phosphorylation of various membrane proteins. Ca(2+)-handling abnormalities in the diabetic heart occur mainly due to defects in sarcolemmal Na(+)-K(+) ATPase, Na(+)-Ca(2+) exchange, Na(+)-H(+) exchange, Ca(2+)-channels and Ca(2+)-pump activities as well as changes in sarcoplasmic reticular Ca(2+)-uptake and Ca(2+)-release processes; these alterations may lead to the occurrence of intracellular Ca(2+) overload. Metabolic defects due to insulin deficiency or ineffectiveness as well as hormone imbalance in diabetes are primarily associated with a shift in substrate utilization and changes in the oxidation of fatty acids in cardiomyocytes. Mitochondria initially seem to play an adaptive role in serving as a Ca(2+) sink, but the excessive utilization of long-chain fatty acids for a prolonged period results in the generation of oxidative stress and impairment of their function in the diabetic heart. In view of the activation of sympathetic nervous system and renin-angiotensin system as well as platelet aggregation, endothelial dysfunction and generation of oxidative stress in diabetes and blockade of their effects have been shown to attenuate subcellular remodeling, metabolic derangements and signal transduction abnormalities in the diabetic heart. On the basis of these observations, it is suggested that oxidative stress and subcellular remodeling due to hormonal imbalance and metabolic defects play a critical role in the genesis of heart failure during the development of diabetic cardiomyopathy.
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Affiliation(s)
- Naranjan S Dhalla
- Department of Physiology, Faculty of Medicine, Institute of Cardiovascular Sciences, St. Boniface Hospital Research, University of Manitoba, 351 Tache Avenue, Winnipeg, MB, R2H 2A6, Canada,
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8
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Reed G, Cefaratti C, Berti-Mattera LN, Romani A. Lack of insulin impairs Mg2+ homeostasis and transport in cardiac cells of streptozotocin-injected diabetic rats. J Cell Biochem 2008; 104:1034-53. [DOI: 10.1002/jcb.21690] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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9
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Täng MS, Haugen E, Isic A, Fu M, Andersson B. Influence of Age, Hypertension, and Diabetes on Cardiac Reserve in a Rat Model. J Am Soc Echocardiogr 2007; 20:731-7. [DOI: 10.1016/j.echo.2006.11.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2006] [Indexed: 10/23/2022]
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10
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Nemoto O, Kawaguchi M, Yaoita H, Miyake K, Maehara K, Maruyama Y. Left ventricular dysfunction and remodeling in streptozotocin-induced diabetic rats. Circ J 2006; 70:327-34. [PMID: 16501301 DOI: 10.1253/circj.70.327] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND It is not fully clarified how diabetes mellitus (DM)-induced cardiac dysfunction is associated with histopathological changes of the heart in a long lasting period of DM. METHODS AND RESULTS Eighteen weeks after a streptozotocin injection was given to Wistar - Kyoto rats (D rats), echocardiography and hemodynamic studies including the dobutamine infusion test were performed. After perfusion fixation, immunofluorescent staining and histopathology of the heart were analyzed, and analysis with electron microscopy was also conducted. Systolic blood pressure in the conscious state and left ventricular (LV) ejection fraction by 2-dimensional echocardiography were reduced in D rats. LV mechanical responses to dobutamine assessed by maximal LV pressure derivative (+LVdP/dt) also decreased with higher dobutamine doses in D rats. Although LV and right ventricular (RV) wall thickness were smaller in D rats, there were increased RV volumes, indicating LV and RV dilatational remodeling in D rats. The cardiomyocyte transverse diameter and actin staining in cardiomyocytes in both the LV and RV were significantly reduced, and capillary tortuosity and type IV collagen were increased, indicating microangiopathy in D rats. CONCLUSIONS Advanced insulin-dependent DM incurred not only RV remodeling but also overt resting LV systolic dysfunction and decreased LV responsiveness to beta adrenergic stimulation with dilatational remodeling, accompanied by pathological changes of capillaries and cardiomyocytes including actin filaments.
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Affiliation(s)
- Osamu Nemoto
- First Department of Internal Medicine, Fukushima Medical University, Japan
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11
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Watanuki S, Matsuda N, Sakuraya F, Jesmin S, Hattori Y. Protein kinase C modulation of the regulation of sarcoplasmic reticular function by protein kinase A-mediated phospholamban phosphorylation in diabetic rats. Br J Pharmacol 2003; 141:347-59. [PMID: 14691046 PMCID: PMC1574184 DOI: 10.1038/sj.bjp.0705455] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
1. The goal of this study was to elucidate the possible mechanisms by which protein kinase A (PKA)-mediated regulation of the sarcoplasmic reticulum (SR) via phospholambin protein phosphorylation is functionally impaired in streptozotocin-induced diabetic rats. 2. Phospholamban (PLB) protein and mRNA levels were 1.3-fold higher in diabetic than in control hearts, while protein expression of cardiac SR Ca(2+)-ATPase (SERCA2a) was unchanged. 3. Basal and isoprenaline-stimulated phosphorylation of PLB at Ser(16) or Thr(17) was unchanged in diabetic hearts. However, stronger immunoreactivity was observed at the basal level in diabetic hearts when antiphosphoserine antibody was used. 4. Basal (32)P incorporation into PLB was significantly higher in diabetic than in control SR vesicles, but the extent of the PKA-mediated increase in PLB phosphorylation was the same in the two groups of vesicles. 5. Stimulation of Ca(2+) uptake by PKA-catalyzed PLB phosphorylation was weaker in diabetic than in control SR vesicles. The PKA-induced increase in Ca(2+) uptake was attenuated when control SR vesicles were preincubated with protein kinase C (PKC). 6. PKC activities were increased by more than two-fold in the membranous fractions from diabetic hearts in comparison with control values, regardless of whether Ca(2+) was present. This was associated with increases in the protein content of PKCdelta, PKCeta, PKCiota, and PKClambda in diabetic membranous fractions. 7. The changes observed in diabetic rats were reversed by insulin therapy. 8. These results suggest that PKA-dependent phosphorylation may incompletely counteract the function of PLB as an inhibitor of SERCA2a activity in diabetes in which PKC expression and activity are enhanced.
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Affiliation(s)
- Satoko Watanuki
- Department of Pharmacology, Hokkaido University School of Medicine, N-15 W-7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan
| | - Naoyuki Matsuda
- Department of Pharmacology, Hokkaido University School of Medicine, N-15 W-7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan
- Department of Anesthesiology & Critical Care Medicine, Hokkaido University School of Medicine, N-15 W-7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan
| | - Fumika Sakuraya
- Department of Anesthesiology & Critical Care Medicine, Hokkaido University School of Medicine, N-15 W-7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan
| | - Subrina Jesmin
- Department of Cardiovascular Medicine, Hokkaido University School of Medicine, N-15 W-7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan
| | - Yuichi Hattori
- Department of Pharmacology, Hokkaido University School of Medicine, N-15 W-7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan
- Author for correspondence:
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Abstract
Regular physical activity promotes cardiorespiratory fitness and has been considered a cornerstone for non-pharmacological treatment of more than 17 million Americans with diabetes mellitus. Physical exercise has been shown to positively affect certain cardiovascular risk factors such as insulin resistance, glucose metabolism, blood pressure and body fat composition, which are closely associated with diabetes and heart disease. With the increasingly sedentary life style in our society, routine daily exercise of moderate intensity is highly recommended to reduce cardiovascular risk, the leading cause of death in diabetic patients. Exercise produces many beneficial effects to the heart function such as reduced incidence of coronary heart disease, attenuated severity of diabetic cardiomyopathy, improved cardiac performance, cardiac reserve and autonomic regulation. Nevertheless, many diabetic patients do not appear to gain much benefit from exercise or may even be at risk of performing physical exercise. This review summarizes the benefit and risk of exercise on diabetic heart function, with a special emphasis on myocardial and autonomic function.
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Affiliation(s)
- Shiyan Li
- Division of Pharmaceutical Sciences and Graduate Neuroscience Program, University of Wyoming College of Health Sciences, P.O. Box 3375, Laramie, WY 82071-3375, USA
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Hrbasová M, Novotny J, Hejnová L, Kolár F, Neckár J, Svoboda P. Altered myocardial Gs protein and adenylyl cyclase signaling in rats exposed to chronic hypoxia and normoxic recovery. J Appl Physiol (1985) 2003; 94:2423-32. [PMID: 12736191 DOI: 10.1152/japplphysiol.00958.2002] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The present work has analyzed the consequences of chronic intermittent high-altitude hypoxia for functioning of the G protein-mediated adenylyl cyclase (AC) signaling system in the right (RV) and left ventricular (LV) myocardium in rats. Adaptation to hypoxia did not appreciably affect the number of beta-adrenoceptors and the content of predominantly membrane-bound alpha-subunit (G(s)alpha) of the stimulatory G protein, but it raised the amount of cytosolic G(s)alpha in RV. The levels of myocardial inhibitory Galpha protein were not altered. Activity of AC stimulated by GTP, fluoride, forskolin, or isoprotertenol was reduced by approximately 50% in RV from chronically hypoxic rats, and a weaker depression was also found in LV. In addition, hypoxia significantly diminished a functional activity of membrane-bound G(s)alpha in both RV and LV. The RV baseline contractile function was markedly increased in chronically hypoxic animals, and its sensitivity to beta-adrenergic stimulation was decreased. Animals recovering from hypoxia for 5 wk still exhibited markedly elevated levels of cytosolic G(s)alpha and significantly lower activity of AC in RV than did age-matched controls, but contractile responsiveness to beta-agonists was normal.
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Affiliation(s)
- Markéta Hrbasová
- Faculty of Natural Sciences, Department of Physiology and Developmental Biology, Charles University, Vinicna 7, Prague 2, Czech Republic
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14
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Abstract
Patients with diabetes mellitus have an increased morbidity and mortality from cardiovascular disease. Both coronary artery disease and congestive heart failure (CHF) are largely responsible for the increased cardiovascular adverse events in patients with diabetes. This review discusses the pathophysiology of CHF, the mechanisms of left ventricular (LV) dysfunction and the neurohormonal mechanisms involved in both LV dysfunction and CHF. Diabetes with and without hypertension is an important cause of LV dysfunction and CHF. Diabetes may be responsible for the metabolic and ultrastructural causes of LV dysfunction, while hypertension may be responsible for the marked fibrotic changes that are found. Experimental induction of diabetes in animals has shed light on the biochemical and ultrastructural changes seen. The role of insulin to reverse both metabolic and structural changes is reviewed both from experimental data and with the limited amount of clinical data available. The therapy of CHF in patients with diabetes is similar to that of patients without diabetes, with therapy directed toward the use of beta-blockers and angiotensin converting enzyme (ACE) inhibitors. As the morbidity and mortality are higher in patients with diabetes, several studies have pointed out the importance of this subgroup where the opportunity to make a significant clinical impact exists. A significant opportunity exists to reduce morbidity and mortality with beta-blockers and ACE inhibitors when ischaemia and CHF are both present. However, studies in patients diabetes have been limited to post hoc subgroup analyses and rarely as predefined subgroups. Clinical trials involving patients with diabetes with and without hypertension and LV dysfunction are clearly needed in the future to adequately address the needs of this high risk subgroup.
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Affiliation(s)
- Steven J Lavine
- Harper Hospital, Wayne State University, Detroit, Michigan, USA.
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15
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Podolin DA, Wills BK, Wood IO, Lopez M, Mazzeo RS, Roth DA. Attenuation of age-related declines in glucagon-mediated signal transduction in rat liver by exercise training. Am J Physiol Endocrinol Metab 2001; 281:E516-23. [PMID: 11500307 DOI: 10.1152/ajpendo.2001.281.3.e516] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
This study investigated alterations in glucagon receptor-mediated signal transduction in rat livers from 7- to 25-mo-old animals and examined the effects of exercise training on ameliorating these changes. Sixty-six young (4 mo), middle-aged (12 mo), and old (22 mo) male Fischer 344 rats were divided into sedentary and trained (treadmill running) groups. Isolated hepatic membranes were combined with [(125)I-Tyr(10)]monoiodoglucagon and nine concentrations of glucagon to determine maximal binding capacity (B(max)) and dissociation constant (K(d)). No alterations were found in B(max) among groups; however, middle-aged trained animals had significantly higher glucagon affinity (lower K(d); 21.1 +/- 1.8 nM) than did their untrained counterparts (50.2 +/- 7.1 nM). Second messenger studies were performed by measuring adenylyl cyclase (AC) specific activity under basal conditions and with four pharmacological stimulations to assess changes in receptor-dependent, G protein-dependent, and AC catalyst-dependent cAMP production. Age-related declines were observed in the old animals under all five conditions. Training resulted in increased cAMP production in the old animals when AC was directly stimulated by forskolin. Stimulatory G protein (G(s)) content was reduced with age in the sedentary group; however, training offset this decline. We conclude that age-related declines in glucagon signaling capacity and responsiveness may be attributed, in part, to declines in intrinsic AC activity and changes in G protein [inhibitory G protein (G(i))/G(s)] ratios. These age-related changes occur in the absence of alterations in glucagon receptor content and appear to involve both G protein- and AC-related changes. Endurance training was able to significantly offset these declines through restoration of the G(i)/G(s) ratio and AC activity.
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Affiliation(s)
- D A Podolin
- University of Colorado, Boulder, CO 80303, USA.
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Stanley WC, Dore JJ, Hall JL, Hamilton CD, Pizzurro RD, Roth DA. Diabetes reduces right atrial β-adrenergic signaling but not agonist stimulation of heart rate in swine. Can J Physiol Pharmacol 2001. [DOI: 10.1139/y00-133] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
This study assessed the effects of streptozotocin diabetes in swine on the heart rate response to β-adrenergic stimulation the adenylyl cyclase signal transduction pathway. Diabetic animals (n = 9) were hyperglycemic compared to the control group (n = 10) (12.6 ± 1.0 vs. 3.53 ± 0.29 mM). There were no significant differences between the diabetic and nondiabetic groups in the heart rate response to isoproterenol, however, there was a significant reduction (14%) in β-adrenergic receptor density in the right atrium in the diabetic (61 ± 3 fmol/mg protein) versus the nondiabetic group (71 ± 3) (P < 0.05). The content of guanosine triphosphate binding regulatory proteins (Gs and Gi) in the right atrium was not affected by diabetes, nor was adenylyl cyclase activity under unstimulated conditions or with receptor-dependent stimulation with isoproterenol. On the other hand, adenylyl cyclase activity was 34% lower when directly stimulated with forskolin, and it was reduced by 23% when stimulated through Gs with Gpp(NH)p. In conclusion, beta-adrenergic stimulation of heart rate with isoproteronol and the receptor-dependent signal transduction pathway remained intact in the right atrium of diabetic swine despite reduced beta-adrenergic receptor density, G-protein content, and direct stimulation of adenylyl cyclase activity.Key words: diabetes, G-proteins, heart rate, receptors, signal transduction.
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17
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Dinçer UD, Bidasee KR, Güner S, Tay A, Ozçelikay AT, Altan VM. The effect of diabetes on expression of beta1-, beta2-, and beta3-adrenoreceptors in rat hearts. Diabetes 2001; 50:455-61. [PMID: 11272160 DOI: 10.2337/diabetes.50.2.455] [Citation(s) in RCA: 134] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Diabetic hearts exhibit decreased responsiveness to stimulation by beta-adrenoreceptor (beta-AR) agonists. This decrease in activity may be due to changes in expression and/or signaling of beta-AR. Recently we showed that right atrial strips from 14-week streptozotocin (STZ)-induced diabetic rat hearts exhibit decreased responsiveness to beta1-AR agonist stimulation, but not to beta2-AR agonist. In the present study, we investigated the effects of long-term diabetes on the expression of cardiac beta1-, beta2-, and beta3-ARs and looked at whether these changes could be restored with insulin treatment. Using reverse transcription-polymerase chain reaction (RT-PCR), PAGE, and Western blot analysis, we found that beta1-AR mRNA and protein levels decreased by 34.9 +/- 5.8 and 44.4 +/- 5.8%, respectively, in 14 week-STZ-treated diabetic rat hearts when compared with age-matched controls. On the other hand, mRNA levels encoding beta2- and beta3-ARs increased by 72.5 +/- 16.6 and 97.3 +/- 26.1%, respectively. Although the latter translated into a proportional increase in beta3-AR protein levels (100.0 +/- 17.0%), beta2-AR protein levels decreased to 82.6 +/- 1.1% of control. Insulin treatment for 2 weeks, after 12 weeks of untreated diabetes, partially restored beta1-AR mRNA and protein levels to 60.1 +/- 8.4 and 83.2 +/- 5.0%, respectively, of control. Although insulin treatment minimally attenuated the rise in mRNA levels encoding beta2- and beta3-ARs, the steady-state levels of these proteins returned to near control values. These data suggest that the decreased responsiveness of diabetic hearts to stimulation of beta-AR agonists may be due to a decrease in beta1-AR and an increase beta3-AR expression.
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Affiliation(s)
- U D Dinçer
- Department of Pharmacology, Faculty of Pharmacy, University of Ankara, Turkey
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18
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Roth DA, White CD, Podolin DA, Mazzeo RS. Alterations in myocardial signal transduction due to aging and chronic dynamic exercise. J Appl Physiol (1985) 1998; 84:177-84. [PMID: 9451633 DOI: 10.1152/jappl.1998.84.1.177] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Normal aging without disease leads to diminished chronotropic and inotropic responses to catecholamine stimulation, resulting in depressed cardiac function with stress. The purpose of this study was to determine molecular mechanisms for decrements in adrenergic responsiveness of the left ventricle (LV) due to aging and to study the effects of chronic dynamic exercise on signal transduction. We measured beta-adrenergic receptor (beta-AR) density, adenylyl cyclase (AC) activity, and G-protein content and distribution in LV from 66 male Fischer 344 rats from three age groups that were either sedentary or treadmill trained (60 min/days, 5 days/wk, 10 wk at 75% of the maximal capacity). Final ages were 7 mo (young), 15 mo (middle-age), and 25 mo (old). There was no significant difference in beta-AR density among groups as a function of age or training. AC production of adenosine 3',5'-cyclic monophosphate (cAMP) with the use of five pharmacological stimulations revealed that old sedentary myocardium had depressed basal, receptor-dependent, G-protein-dependent, and AC catalyst stimulation (30-43%) compared with hearts from young and middle-age sedentary rats. Training did not alter AC activity in either middle-age or old groups but did increase G-protein-dependent cAMP production in young myocardium (12-34%). Immunodetectable concentrations of stimulatory and inhibitory G proteins (Gs and Gi, respectively) showed 43% less total Gs with similar Gi content in hearts from old sedentary compared with middle-age sedentary rats. When compared with young sedentary animals, Gi content was 39 and 50% higher in middle-age sedentary and old sedentary myocardium, respectively. With age, there was a significant shift in the alpha-subunit of Gs distribution from cytosolic fractions of LV homogenates to membrane-bound fractions (8-12% redistribution in middle-age sedentary vs. old sedentary). The most significant training effect was a decrease in Gi content in hearts from old trained rats (23%), which resulted in values comparable with young sedentary rats and reduced the Gi/Gs ratio by 27% in old-rat LV. We report that age-associated reductions in cardiovascular beta-adrenergic responsiveness correspond with alterations in postreceptor adrenergic signaling rather than with a decrease in receptor number. Chronic dynamic exercise partially attenuates these reductions through alterations in postreceptor elements of cardiac signal transduction.
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Affiliation(s)
- D A Roth
- Department of Kinesiology, University of Colorado, Boulder 80309-0354, USA
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19
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Stanley WC, Hall JL, Hacker TA, Hernandez LA, Whitesell LF. Decreased myocardial glucose uptake during ischemia in diabetic swine. Metabolism 1997; 46:168-72. [PMID: 9030824 DOI: 10.1016/s0026-0495(97)90297-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
The purpose of the study was to assess myocardial glucose uptake in nondiabetic (n = 5) and streptozotocin-diabetic (n = 6) Yucatan miniature swine under matched hyperglycemic and hypoinsulinemic conditions. Fasting conscious diabetic swine had significantly higher plasma glucose levels (20.9 +/- 2.6 v 5.2 +/- 0.3 mmol/L) and lower insulin levels (6 +/- 1 v 14 +/- 4 microU/mL) than nondiabetic animals. Myocardial glucose uptake was measured in open-chest anesthetized animals under aerobic and ischemic conditions 12 weeks after streptozotocin treatment. Coronary blood flow was controlled by an extracorporeal perfusion circuit. Ischemia was induced by reducing left anterior descending (LAD) coronary artery blood flow by 60% for 40 minutes. Animals were treated with somatostatin to suppress insulin secretion, and nondiabetic swine received intravenous (IV) glucose to match the hyperglycemia in the diabetic animals. The rate of glucose uptake by the myocardium was not statistically different under aerobic conditions, but was significantly lower in diabetic swine during ischemia (0.20 +/- 0.08 v 0.63 +/- 0.14 micromol x g(-1) x min(-1), P < .01). Myocardial glucose transporter (GLUT4) protein concentration was decreased by 31% in diabetic swine. In conclusion, 12 weeks of streptozotocin diabetes in swine caused a significant decrease in myocardial GLUT4 protein and a decrease in myocardial glucose uptake during ischemia.
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Affiliation(s)
- W C Stanley
- Section of Cardiovascular Pharmacology, Syntex Discovery Research, Palo Alto, CA, USA
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