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Objective Coronary heart disease and diabetes are highly prevalent among obese populations due to aberrant dietary cholesterol metabolism. Here we investigated the effect of heat shock factor-1 (HSF-1) on atherosclerosis and dietary cholesterol metabolism. Method and Results: Atherogenic western diet-induced weight gain was reduced in HSF-1 and LDLr double knock out mice (HSF-1 –/– /LDLr –/– ), compared to LDLr –/– mice. Atherosclerotic lesion growth in aortic arch and carotid regions was retarded. Also, repression of PPAR-γ2 and AMPKα expression in adipose tissue, low hepatic steatosis, and lessened plasma adiponectins and lipoproteins were observed. Furthermore, reduced heat shock proteins and their mRNA levels in atherosclerotic lesions correlated with reduction in lesion burden. In HSF-1 –/– /LDLr –/– liver, higher cholesterol 7α hydroxylase (CYP7A1, the rate limiting enzyme in the synthesis of bile acid from cholesterol) and MDR1/p-glycoprotein (bile salt transporter across the hepatocyte canalicular membrane) gene expressions were observed, consistent with higher bile acid sequestration and larger hepatic bile ducts. HSF-1 deletion, however, upregulated both CYP7A1 enzyme and MDR1/p-glycoportein expression and activities, due to removal of its repressive binding in the CYP7A1 and MDR1 gene promoters. This increased the conversion of cholesterol into 7-α-hydroxycholesterol and bile acid, and dietary cholesterol metabolism. Conclusion HSF-1 ablation not only eliminates heat shock response to retard atherosclerosis, but it also transcriptionally upregulates CYP7A1 and MDR1/P-gp axis to increase cholesterol metabolism. Therefore, HSF-1 is a metabolic regulator of dietary cholesterol and a major contributor to heart disease among obese population. [ABSTRACT FROM AUTHOR]

Cardiomyocyte apoptosis is known to contribute to myocardial ischemia/reperfusion (I/R) injury. Caspase recruitment domain-containing protein 9 (CARD9) play a role in cardiac fibrosis and dysfunction. However, the role of CARD9 in apoptosis of cardiomyocytes in myocardial I/R injury and its underlying mechanisms are still unclear. In this study, CARD9 expression was found to increase in H9c2 cells in response to hydrogen peroxide. Loss of CARD9 significantly increased caspase-3 activation and cardiomyocyte death following oxidative stress in vitro. Conversely, CARD9 overexpression decreased apoptosis as evidenced by a reduction in caspase-3 activation and the apoptotic rate. The caspase recruitment domain (CARD) of CARD9 was necessary for the protective effect of CARD9 against oxidative stress in cardiomyocytes. CARD9 suppressed the activation of caspase-9 by interacting with Apaf-1 via its CARD domain in H9c2 cells exposed to H 2 O 2. Ablation of caspase-9 activity by z-lehd-fmk effectively prevented the detrimental effect of CARD9 deficiency on cardiomyocytes. Wild-type (WT) and CARD9−/− mice were subjected to 30 min of left ascending coronary (LAD) ischemia and 12 h of reperfusion. TdT-mediated dUTP nick end labeling (TUNEL) staining analysis showed that CARD9−/− mice exhibited a significantly higher number of apoptotic-positive cells after myocardial I/R injury than the WT mice. These results suggest that CARD9 protects cardiomyocytes from apoptosis by interacting with Apaf-1 and interfering with apoptosome formation following myocardial I/R injury in vivo and in vitro. Image 1 • CARD9 overexpression protects cardiomyocytes from apoptosis-induced by H 2 O 2. • CARD9 deficiency aggravates cardiomyocyte apoptosis following myocardial I/R injury. • CARD9 is involved in regulating cardiomyocyte apoptosis by interacting with Apaf-1. [ABSTRACT FROM AUTHOR]