HDAC Inhibition Attenuates Inflammatory, Hypertrophic, and Hypertensive Responses in Spontaneously Hypertensive Rats

Abstract

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...

Antihypertensive Effects of Peroxisome Proliferator-Activated Receptor-β Activation in Spontaneously Hypertensive Rats

“…9 The anti-inflammatory effects of PPAR-␤ could be related to the blood pressure-lowering effect. However, additional mechanisms must be involved, because antihypertensive drugs like hydralazine do not reduce proinflammatory cytokines, 35 and PPAR␤ agonists also exert anti-inflammatory effects in vitro as well. 20 Vascular microarray profiling in 2 models of hypertension, including SHRs, identified caveolin 1, RGS2, and RGS5 as key antihypertensive targets.…”

Signaling effectors underlying pathologic growth and remodeling of the heart

“…This effect may be more specific to HDAC1, -2, or -3, as the more selective class I HDAC inhibitor apicidin suppresses cardiac hypertrophy and improves function in a mouse model of pressure overload (131). HDAC inhibitors also reduce fibrosis and negative remodeling of the heart after myocardial infarction injury in the rat, as well as in rat models of spontaneous and salt-sensitive hypertension (132)(133)(134). These results are consistent with genetic studies in Hdac2-null mice, which show less cardiac hypertrophy induced by various pathologic stimuli (135).…”

HDAC4 mediates development of hypertension via vascular inflammation in spontaneous hypertensive rats

“…A recent study clarified that the class I and IIa HDACs play critical roles in mediating cardiac hypertrophy. For example, HDAC2 was activated by hypertrophic stresses in association with the induction of heat shock protein 70 (17), mice lacking HDAC5 and/or HDAC9 exhibited exacerbated cardiac hypertrophy in response to stress induced by aortic stenosis (26,27), an inhibitor of class I HDACs valproic acid attenuated cardiac hypertrophy in SHR (5). On the other hand, it was reported that HDAC4 is predominantly associated with muscle and chondrocyte development (28,50).…”