The mature aortic valve is composed of a structured trilaminar extracellular matrix that is interspersed with aortic valve interstitial cells (AVICs) and covered by endothelium. Dysfunction of the valvular endothelium initiates calcification of neighboring AVICs leading to calcific aortic valve disease (CAVD). The molecular mechanism by which endothelial cells communicate with AVICs and cause disease is not well understood. Using a co-culture assay, we show that endothelial cells secrete a signal to inhibit calcification of AVICs. Gain or loss of nitric oxide (NO) prevents or accelerates calcification of AVICs, respectively, suggesting that the endothelial cell-derived signal is NO. Overexpression of Notch1, which is genetically linked to human CAVD, retards the calcification of AVICs that occurs with NO inhibition. In AVICs, NO regulates the expression of Hey1, a downstream target of Notch1, and alters nuclear localization of Notch1 intracellular domain. Finally, Notch1 and NOS3 (endothelial NO synthase) display an in vivo genetic interaction critical for proper valve morphogenesis and the development of aortic valve disease. Our data suggests that endothelial cell-derived NO is a regulator of Notch1 signaling in AVICs in the development of the aortic valve and adult aortic valve disease.

Abstract-Reactive oxygen species and proinflammatory cytokines contribute to cardiovascular diseases. Inhibition of downstream transcription factors and gene modifiers of these components are key mediators of hypertensive response. Histone acetylases/deacetylases can modulate the gene expression of these hypertrophic and hypertensive components. Therefore, we hypothesized that long-term inhibition of histone deacetylase with valproic acid might attenuate hypertrophic and hypertensive responses by modulating reactive oxygen species and proinflammatory cytokines in SHR rats. Seven-week-old SHR and WKY rats were used in this study. Following baseline blood pressure measurement, rats were administered valproic acid in drinking water (0.71% wt/vol) or vehicle, with pressure measured weekly thereafter. Another set of rats were treated with hydralazine (25 mg/kg per day orally) to determine the pressure-independent effects of HDAC inhibition on hypertension. Following 20 weeks of treatment, heart function was measured using echocardiography, rats were euthanized, and heart tissue was collected for measurement of total reactive oxygen species, as well as proinflammatory cytokine, cardiac hypertrophic, and oxidative stress gene and protein expressions. Blood pressure, proinflammatory cytokines, hypertrophic markers, and reactive oxygen species were increased in SHR versus WKY rats. These changes were decreased in valproic acid-treated SHR rats, whereas hydralazine treatment only reduced blood pressure. These data indicate that long-term histone deacetylase inhibition, independent of the blood pressure response, reduces hypertrophic, proinflammatory, and hypertensive responses by decreasing reactive oxygen species and angiotensin II type1 receptor expression in the heart, demonstrating the importance of uncontrolled histone deacetylase activity in hypertension. (Hypertension. 2010;56:437-444.)Key Words: Ang II Ⅲ cardiac hypertrophy Ⅲ cytokines Ⅲ hypertension Ⅲ oxidative stress Ⅲ HDAC E ssential hypertension is a condition associated with increased expression of proinflammatory cytokines (PICs). 1,2 Studies from our laboratory and others have shown that PICs lead to an increase in reactive oxygen species (ROS), which upregulates nuclear factor (NF)B activity, thus further increasing PIC and ROS transcription and amplifying their subsequent actions. [3][4][5] Along with renin-angiotensin system (RAS) components, PICs also activate hypertrophic mediators, which can result in cardiac hypertrophy and altered cardiac remodeling and function. 6,7 There are many triggers of hypertensive-induced inflammation resulting in both hypertrophic and hypertensive responses, many of which are through transcription factor NFB activation, ultimately resulting in alterations of gene transcription and perpetuation of the hypertensive state. 5,8 For transcription factors such as NFB to activate their target genes, DNA and chromatin remodeling must occur. Posttranslational modifications of histone cores through a tightly regulated addition/re...

This study, for the first time, demonstrates that proinflammatory cytokines modulate neurotransmitters in the PVN and contribute to sympathoexcitation in HF.

This study demonstrates that NF-kappaB blockade with PDTC mitigates oxidative stress and improves mitochondrial structural integrity directly, through down-regulation of increased oxygen-free radicals, thereby increasing ATP synthesis and thus restoring cardiac function in type II diabetes.