Novel mechanism of angiotensin II-induced cardiac injury in hypertensive rats: the critical role of ASK1 and VEGF

Abstract

This study was undertaken to elucidate a novel mechanism underlying angiotensin II-induced cardiac injury, focusing on the role of oxidative stress and myocardial capillary density. Salt-loaded Dahl salt-sensitive hypertensive rats (DS rats), a useful model for hypertensive cardiac remodeling or heart failure, were orally given irbesartan (an AT1 receptor blocker), tempol (a superoxide dismutase mimetic) or hydralazine (a vasodilator). Irbesartan significantly ameliorated left ventricular ischemia and prevented the development of cardiac hypertrophy and fibrosis in DS rats. The benefits were associated with the attenuation of oxidative stress, normalization of myocardial capillary density and inhibition of capillary endothelial apoptosis. Moreover, DS rats with significant cardiac hypertrophy and fibrosis displayed decreased myocardial vascular endothelial growth factor (VEGF) expression and increased cardiac apoptosis signal-regulating kinase 1 (ASK1) activation. Treatment with irbesartan significantly reversed these phenotypes. Tempol treatment of DS rats mimicked all the above-mentioned effects of irbesartan, indicating the critical role of oxidative stress in cardiac injury. We also investigated the role of VEGF and ASK1 in oxidative stress-induced endothelial apoptosis by using cultured endothelial cells from wild-type and ASK1-deficient mice. Oxidative stress-induced ASK1 activation led to endothelial apoptosis, and VEGF treatment prevented oxidative stress-induced endothelial apoptosis by inhibiting ASK1 activation. We obtained the first evidence that oxidative stress-induced cardiac VEGF repression and ASK1 activation caused the enhancement of endothelial apoptosis and contributed to a decrease in myocardial capillary density. These effects resulted in angiotensin II-induced progression of cardiac injury.

Enhanced Angiotensin II-Induced Cardiac and Aortic Remodeling in ACE2 Knockout Mice

“…It has been confirmed that O 2 ‾ is the dominant ROS species in ACE2 KO heart (Oudit et al, 2007). Interestingly, Nako et al reported that irbesartan (AT1R blocker) and Tempol (free radical scavenger) display the same 52 cardioprotective effects against Ang II induced cardiac injury (Nako et al, 2012). Present study results show that there was enhanced O 2 ‾ production in the myocardium and aorta of ACE2 KO mice infused with Ang II.…”

“…Support is greatest for the first theory (Crackower et al, 2002;Nakamura et al, 2008;Nako et al, 2012), however, there is still evidence that Ang (1-7) is essential for maintenance of normal cardiac function by counteracting Ang II induced hypertrophic effects (Grobe et al, 2007;Kassiri et al, 2009b There are questions as to the mechanisms by which Ang II induces cardiac injury. One proposed mechanism is increased sarcolemmic and microvascular permeability leading to cardiac myocyte death (Gavras & Gavras, 2002b).…”

R-CHOP with or without bevacizumab in patients with previously untreated diffuse large B-cell lymphoma: final MAIN study outcomes

“…Our findings, together with those of others, [29][30][31][32][33][34][35][36][37] do not support further evaluation of combination treatment with bevacizumab plus R-CHOP in patients with DLBCL. Indeed, it has been suggested that the tumor microenvironment may be predictive of a response to bevacizumab in DLBCL, and that bevacizumab may only be beneficial in DLBCL with high relative expression of a suite of endothelial markers and angiogenic regulators (the 'stromal-2' signature) that is associated with increased tumor blood vessel density.…”

“…33 VEGF, in turn, has a cardioprotective role. It is up-regulated in both animal and human hearts exposed to hypoxic conditions [34][35][36] and can prevent oxidative stress-induced apoptosis of endothelial cells in vitro. 29 Thus, it may be that bevacizumab is not directly toxic to the heart, but rather its inhibition of endothelial VEGF expression prevents the ability of VEGF to counter the negative effects of doxorubicin.…”

Hypoxic Preconditioning Increases the Neuroprotective Effects of Mesenchymal Stem Cells in a Rat Model of Spinal Cord Injury

“…Reactive oxygen species-induced activation of apoptosis signalregulating kinase 1 (ASK1) plays crucial roles in oxidative stressmediated cell death [51]. Nako et al reported that VEGF treatment prevents oxidative stress-induced endothelial apoptosis by inhibiting activation of ASK [52]. In addition, VEGF upregulates the expression of Becn1, which is an autophagy-related gene [44].…”