ANG II promotes IGF-IIR expression and cardiomyocyte apoptosis by inhibiting HSF1 via JNK activation and SIRT1 degradation

Abstract

Hypertension-induced cardiac hypertrophy and apoptosis are major characteristics of early-stage heart failure. Our previous studies found that the activation of insulin-like growth factor receptor II (IGF-IIR) signaling was critical for hypertensive angiotensin II (ANG II)-induced cardiomyocyte apoptosis. However, the detailed mechanism by which ANG II regulates IGF-IIR in heart cells remains elusive. In this study, we found that ANG II activated its downstream kinase JNK to increase IGF-IIR expression through the ANG II receptor angiotensin type 1 receptor. JNK activation subsequently led to sirtuin 1 (SIRT1) degradation via the proteasome, thus preventing SIRT1 from deacetylating heat-shock transcription factor 1 (HSF1). The resulting increase in the acetylation of HSF1 impaired its ability to bind to the IGF-IIR promoter region (nt À 748 to À 585). HSF1 protected cardiomyocytes by acting as a repressor of IGF-IIR gene expression, and ANG II diminished this HSF1-mediated repression through enhanced acetylation, thus activating the IGF-IIR apoptosis pathway. Taken together, these results suggest that HSF1 represses IGF-IIR gene expression to protect cardiomyocytes. ANG II activates JNK to degrade SIRT1, resulting in HSF1 acetylation, which induces IGF-IIR expression and eventually results in cardiac hypertrophy and apoptosis. HSF1 could be a valuable target for developing treatments for cardiac diseases in hypertensive patients. Apoptosis has been implicated in a wide variety of cardiovascular disorders, including myocardial infarction and heart failure, suggesting that activation of apoptotic pathways contributes to cardiomyocyte loss and subsequently cardiac dysfunction. Previous studies reported that several extracellular molecules, such as insulin-like growth factors (IGFs) and angiotensin II (ANG II), are involved in the development of cardiac hypertrophy and apoptosis.

Olmesartan Prevents Microalbuminuria in db/db Diabetic Mice Through Inhibition of Angiotensin II/p38/SIRT1-Induced Podocyte Apoptosis

“…Specific deletion of SIRT1 in podocytes increased podocyte loss and worsened albuminuria through enhancing the acetylation status and activation of downstream transcription factors [6]. Angiotensin II decreases SIRT1 expression in endothelial cells [11,22]. Therefore we hypothesized that angiotensin II blockade by olmesartan prevents albuminuria in diabetic nephropathy through modulating SIRT1 mediated podocyte viability.…”

Environmental tobacco smoke increases autophagic effects but decreases longevity associated with Sirt-1 protein expression in young C57BL mice hearts

“…Enhanced IGF2R expression will cause cardiac hypertrophy and cardiomyocytes apoptosis. [30]. This result suggested that the IGF2R signaling pathway played an important role in the development of cardiac hypertrophy.…”

HSF1 Relieves Amyloid-β-Induced Cardiomyocytes Apoptosis

“…Li et al reported that up-regulation of HSF1 by atorvastatin inhibited AGEinduced apoptosis [18], and Dai et al demonstrated that activation of HSF1 by CHIP protected cells against apoptosis [28], these reports are similar to our results. At the meanwhile, 2,4-bis(4-hydroxybenzyl) phenol and ANG II are reported to sensitize cells to apoptosis by inhibiting HSF1 [29,30]. It seems that HSF1 can attenuate cell injuries induced by multiple factors.…”

“…Amyloid-b (Ab [25][26][27][28][29][30][31][32][33][34][35] ) was purchased from Bioss (Beijing, China) and dissolved in sterile water at the concentration of 0.94 mM. This stock solution was stored at -20°C but was kept at 37°C for 72 h before use.…”