Heart angiotensin II-induced cardiomyocyte hypertrophy suppresses coronary angiogenesis and progresses diabetic cardiomyopathy

Abstract

Heart angiotensin II-induced cardiomyocyte hypertrophy suppresses coronary angiogenesis and progresses diabetic cardiomyopathy. Am J Physiol Heart Circ Physiol 302: H1871-H1883, 2012. First published March 2, 2012; doi:10.1152/ajpheart.00663.2011.-To examine whether and how heart ANG II influences the coordination between cardiomyocyte hypertrophy and coronary angiogenesis and contributes to the pathogenesis of diabetic cardiomyopathy, we used Spontaneously Diabetic Torii (SDT) rats treated without and with olmesartan medoxomil (an ANG II receptor blocker). In SDT rats, left ventricular (LV) ANG II, but not circulating ANG II, increased at 8 and 16 wk after diabetes onset. SDT rats developed LV hypertrophy and diastolic dysfunction at 8 wk, followed by LV systolic dysfunction at 16 wk, without hypertension. The SDT rat LV exhibited cardiomyocyte hypertrophy and increased hypoxia-inducible factor-1␣ expression at 8 wk and to a greater degree at 16 wk and interstitial fibrosis at 16 wk only. In SDT rats, coronary angiogenesis increased with enhanced capillary proliferation and upregulation of the angiogenic factor VEGF at 8 wk but decreased VEGF with enhanced capillary apoptosis and suppressed capillary proliferation despite the upregulation of VEGF at 16 wk. In SDT rats, the phosphorylation of VEGF receptor-2 increased at 8 wk alone, whereas the expression of the antiangiogenic factor thrombospondin-1 increased at 16 wk alone. All these events, except for hyperglycemia or blood pressure, were reversed by olmesartan medoxomil. These results suggest that LV ANG II in SDT rats at 8 and 16 wk induces cardiomyocyte hypertrophy without affecting hyperglycemia or blood pressure, which promotes and suppresses coronary angiogenesis, respectively, via VEGF and thrombospondin-1 produced from hypertrophied cardiomyocytes under chronic hypoxia. Thrombospondin-1 may play an important role in the progression of diabetic cardiomyopathy in this model. angiogenic factor; antiangiogenic factor; thrombospondin-1; vascular endothelial growth factor; vascular endothelial growth factor receptor-2 THE RISING INCIDENCE of type 2 diabetes mellitus raises major public health concerns because of the increased risk of cardiovascular complications (1, 2). Diabetic cardiomyopathy (DCM) is defined as left ventricular (LV) dysfunction that occurs independently of coronary artery disease and hypertension (1, 2). Its functional alterations are LV hypertrophy (LVH) and LV diastolic dysfunction, which may precede the development of LV systolic dysfunction (1, 2). Its pathological features involve cardiomyocyte hypertrophy and apoptosis, microvascular pathology, including abnormal capillary density and permeability, and interstitial fibrosis (1, 2, 6).The activation of the renin-angiotensin system (RAS) is well recognized in DCM. The circulating RAS is downregulated in diabetes (24, 35). Nevertheless, pharmacological blockade of the RAS with ANG II type 1 receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors prevents cardiac damage in ...

Pioglitazone Induces Cardiomyocyte Apoptosis and Inhibits Cardiomyocyte Hypertrophy Via VEGFR-2 Signaling Pathway

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Early Administration of Carvedilol Protected against Doxorubicin-Induced Cardiomyopathy

“…Hypertrophic cardiomyopathy can be caused by any disease that increases cardiac afterload and volume overload, some myocardiotoxic drugs, and certain primary genetic disorders of the myocardium (Senni et al, 1998;Roura and Bayes-Genis, 2009;Masuda et al, 2012;Maron et al, 2014;Modesto and Sengupta, 2014;Patel et al, 2015). Without appropriate treatment, hypertrophic cardiomyopathy commonly develops into dilated cardiomyopathy, and ultimately decompensated heart failure (Senni et al, 1998;Roura and Bayes-Genis, 2009;Masuda et al, 2012;Patel et al, 2015).…”

“…Without appropriate treatment, hypertrophic cardiomyopathy commonly develops into dilated cardiomyopathy, and ultimately decompensated heart failure (Senni et al, 1998;Roura and Bayes-Genis, 2009;Masuda et al, 2012;Patel et al, 2015). Doxorubicin (DOX) is used to treat a variety of human neoplasms; however, its usage is limited because of its cardiotoxicity (Blum and Carter, 1974;Von Hoff et al, 1979).…”

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