Renal, retinal and cardiac changes in type 2 diabetes are attenuated by macitentan, a dual endothelin receptor antagonist

Sen, Sabyasachi; Chen, S.; Feng, Biao; Iglarz, Marc; Chakrabarti, Subrata

doi:10.1016/j.lfs.2012.03.032

Cited by 38 publications

(23 citation statements)

References 69 publications

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“…There are very few studies investigating the effect of hyperglycemia on BNP levels. In an experimental study, after 2 and 4 months of diabetes db/db mice developed changes indicative of cardiac failure, and their myocardium showed increased mRNA expression of atrial and BNPs [11]. Treatment with macitentan (dual endothelin receptor antagonist) prevented from such abnormalities.…”

Section: Discussionmentioning

confidence: 99%

The relationship between glycemic control and BNP levels in diabetic patients

Dal¹,

Ata

Yavuz

et al. 2014

Cardiol J

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Section: Discussionmentioning

confidence: 99%

The relationship between glycemic control and BNP levels in diabetic patients

Dal¹,

Ata

Yavuz

et al. 2014

Cardiol J

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“…Experimental evidence suggests that ET-1 expression is induced in experimental models of type 1 and type 2 diabetes [68],[116]. In streptozotocin-induced diabetic mice, endothelial cell-specific loss of ET-1 attenuated myocardial fibrosis, reducing endothelial to mesenchymal transdifferentiation [68]…”

Section: Molecular Signals Implicated In Diabetes-associated Cardimentioning

confidence: 99%

Diabetes-associated cardiac fibrosis: Cellular effectors, molecular mechanisms and therapeutic opportunities

Russo

Frangogiannis

2016

Journal of Molecular and Cellular Cardiology

382

299

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Both type 1 and type 2 diabetes are associated with cardiac fibrosis that may reduce myocardial compliance, contribute to the pathogenesis of heart failure, and trigger arrhythmic events. Diabetes-associated fibrosis is mediated by activated cardiac fibroblasts, but may also involve fibrogenic actions of macrophages, cardiomyocytes and vascular cells. The molecular basis responsible for cardiac fibrosis in diabetes remains poorly understood. Hyperglycemia directly activates a fibrogenic program, leading to accumulation of advanced glycation end-products (AGEs) that crosslink extracellular matrix proteins, and transduce fibrogenic signals through reactive oxygen species generation, or through activation of Receptor for AGEs (RAGE)-mediated pathways. Pro-inflammatory cytokines and chemokines may recruit fibrogenic leukocyte subsets in the cardiac interstitium. Activation of transforming growth factor-β/Smad signaling may activate fibroblasts inducing deposition of structural extracellular matrix proteins and matricellular macromolecules. Adipokines, endothelin-1 and the renin-angiotensin-aldosterone system have also been implicated in the diabetic myocardium. This manuscript reviews our current understanding of the cellular effectors and molecular pathways that mediate fibrosis in diabetes. Based on the pathophysiologic mechanism, we propose therapeutic interventions that may attenuate the diabetes-associated fibrotic response and discuss the challenges that may hamper clinical translation.

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“…Mice fed a high fat diet, but not ob/ob mice, exhibited significantly increased myocardial ET-1 levels suggesting that ET-1 upregulation in obesity may be mediated by leptin (104). In contrast to ob/ob mice, db/db animals had increased levels of myocardial ET-1, perhaps reflecting signaling through the short-form leptin receptor (105). Increased myocardial ET-1 levels in db/db mice are associated with accentuated expression of extracellular matrix proteins (105); however, whether ET-1 plays a crucial role for fibrotic remodeling in this model remains unknown.…”

Section: The Molecular Signals Regulating Obesity-associated Fibrosismentioning

confidence: 99%

Obesity, metabolic dysfunction, and cardiac fibrosis: pathophysiological pathways, molecular mechanisms, and therapeutic opportunities

Cavalera

Wang

Frangogiannis

2014

Translational Research

220

155

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Cardiac fibrosis is strongly associated with obesity and metabolic dysfunction and may contribute to the increased incidence of heart failure, atrial arrhythmias and sudden cardiac death in obese subjects. Our review discusses the evidence linking obesity and myocardial fibrosis in animal models and human patients, focusing on the fundamental pathophysiologic alterations that may trigger fibrogenic signaling, the cellular effectors of fibrosis and the molecular signals that may regulate the fibrotic response. Obesity is associated with a wide range of pathophysiologic alterations (such as pressure and volume overload, metabolic dysregulation, neurohumoral activation and systemic inflammation); their relative role in mediating cardiac fibrosis is poorly defined. Activation of fibroblasts likely plays a major role in obesity-associated fibrosis; however, inflammatory cells, cardiomyocytes and vascular cells may also contribute to fibrogenic signaling. Several molecular processes have been implicated in regulation of the fibrotic response in obesity. Activation of the Renin-Angiotensin-Aldosterone System, induction of Transforming Growth Factor-β, oxidative stress, advanced glycation end-products (AGEs), endothelin-1, Rho-kinase signaling, leptin-mediated actions and upregulation of matricellular proteins (such as thrombospondin-1) may play a role in the development of fibrosis in models of obesity and metabolic dysfunction. Moreover, experimental evidence suggests that obesity and insulin resistance profoundly affect the fibrotic and remodeling response following cardiac injury. Understanding the pathways implicated in obesity-associated fibrosis may lead to development of novel therapies to prevent heart failure and to attenuate post-infarction cardiac remodeling in obese patients.

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Renal, retinal and cardiac changes in type 2 diabetes are attenuated by macitentan, a dual endothelin receptor antagonist

Abstract: These experiments confirmed that ET system plays a significant role in the pathogenesis of chronic complications in type 2 diabetes. Such diabetes induced changes can be reduced macitentan therapy.

Cited by 38 publications

References 69 publications

The relationship between glycemic control and BNP levels in diabetic patients

The relationship between glycemic control and BNP levels in diabetic patients

Diabetes-associated cardiac fibrosis: Cellular effectors, molecular mechanisms and therapeutic opportunities

Obesity, metabolic dysfunction, and cardiac fibrosis: pathophysiological pathways, molecular mechanisms, and therapeutic opportunities

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