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.

Background The aim of this study was to analyse the trends of mortality and causes of death among HIV‐infected patients in Taiwan from 1984 to 2005. Methods Registered data and death certificates for HIV‐infected patients from Taiwan Centers for Disease Control were reviewed. Mortality rate and causes of deaths were compared among patients whose HIV diagnosis was made in three different study periods: before the introduction of highly active antiretroviral therapy (HAART) (pre‐HAART: from 1 January 1984 to 31 March 1997), in the early HAART period (from 1 April 1997 to 31 December 2001), and in the late HAART period (from 1 January 2002 to 31 December 2005). A subgroup of 1161 HIV‐infected patients (11.4%) followed at a university hospital were analysed to investigate the trends of and risk factors for mortality. Results For 10 162 HIV‐infected patients with a mean follow‐up of 1.97 years, the mortality rate of HIV‐infected patients declined from 10.2 deaths per 100 person‐years (PY) in the pre‐HAART period to 6.5 deaths and 3.7 deaths per 100 PY in the early and late HAART periods, respectively (P<0.0001). For the 1161 patients followed at a university hospital (66.8% with CD4 count <200 cells/μL), HAART reduced mortality by 89% in multivariate analysis, and the adjusted hazard ratio for death was 0.28 (95% confidence interval 0.24, 0.33) in patients enrolled in the late HAART period compared with those in the pre‐HAART period. Seventy‐six per cent of the deaths in the pre‐HAART period were attributable to AIDS‐defining conditions, compared with 36% in the late HAART period (P<0.0001). The leading causes of non‐AIDS‐related deaths were sepsis (14.7%) and accidental death (8.3%), both of which increased significantly throughout the three study periods. Compared with patients acquiring HIV infection through sexual contact, injecting drug users were more likely to die from non‐AIDS‐related causes. Conclusions The mortality of HIV‐infected patients declined significantly after the introduction of HAART in Taiwan. In the HAART era, AIDS‐related deaths decreased significantly while deaths from non‐AIDS‐related conditions increased.