Inhibition of Histone Deacetylation Blocks Cardiac Hypertrophy Induced by Angiotensin II Infusion and Aortic Banding

Abstract

Background-A number of distinct stress signaling pathways in myocardium cause cardiac hypertrophy and heart failure.Class II histone deacetylases (HDACs) antagonize several stress-induced pathways and hypertrophy. However, cardiac hypertrophy induced by transgenic overexpression of the homeodomain only protein, HOP, can be prevented by the nonspecific HDAC inhibitors trichostatin A and valproic acid, suggesting that alternate targets that oppose class II HDAC function might exist in myocardium. We tested the effects of several HDAC inhibitors, including a class I HDAC-selective inhibitor, SK-7041, on cardiac hypertrophy induced by angiotensin II (Ang II) treatment or aortic banding (AB). Methods and Results-Cardiac hypertrophy was induced by chronic infusion of Ang II or by AB in mice or rats and evaluated by determining the ratio of heart weight to body weight or to tibia length, cross-sectional area, or echocardiogram. Cardiac hypertrophy induced by Ang II or AB for 2 weeks was significantly reduced by simultaneous administration of trichostatin A, valproic acid, or SK-7041. Echocardiogram revealed that exaggerated left ventricular systolic dimensions were relieved by HDAC inhibitors. HDAC inhibitors partially reversed preestablished cardiac hypertrophy and improved survival of AB mice. The expressions of atrial natriuretic factor, ␣-tubulin, ␤-myosin heavy chain, and interstitial fibrosis were reduced by HDAC inhibition. Conclusions-These results suggest that the predominant effect of HDAC inhibition, mainly mediated by class I HDACs, is to prevent cardiac hypertrophy in response to a broad range of agonist and stretch stimuli.

Specific inhibition of HDAC4 in cardiac progenitor cells enhances myocardial repairs

“…Cardiac sections from infarcted hearts receiving siRNA HDAC4-treated c-kit ϩ CSCs did not demonstrate the formation of tumorigenesis in hearts 6 mo after cell engraftment (data not shown), suggesting that HDAC4 inhibition in c-kit ϩ CSCs does not increase the risk of developing teratomas. In addition, c-kit ϩ CSCs-engrafted MI hearts antagonized cardiac hypertrophy, which is in line with previous observations that inhibition of HDACs showed cardioprotection and blocks cardiac hypertrophy (22,23).…”

Kruppel-like Factor 4 Protein Regulates Isoproterenol-induced Cardiac Hypertrophy by Modulating Myocardin Expression and Activity

“…CM Klf4 KO mice and control mice received a daily oral dose of olmesartan or a daily intraperitoneal injection of TSA during the continuous subcutaneous ISO infusion for 14 days. The doses and the routes of administration for these antihypertrophic reagents were as those employed in previous studies (16,18). Results showed that body weight, systolic blood pressure, and heart rate were unaltered by treatment with olmesartan or TSA, although the diastolic blood pressure was decreased by olmesartan treatment in ISO-untreated CM Klf4 KO mice and control mice (Fig.…”

“…Olmesartan (Daiichi-Sankyo Co. Ltd., Tokyo, Japan) was given by gavage at a dose of 10 mg/kg/day to a subset of mice for 14 days after the surgery (16,17). TSA (Sigma-Aldrich) at 0.6 mg/kg/day was injected intraperitoneally into a subset of mice for 14 days after the surgery (18). For the angiotensin II-induced cardiac hypertrophy model, mice received a subcutaneous infusion of angiotensin II (Sigma-Aldrich) at a rate of 2 mg/kg/day for 14 days, as described previously (19).…”

“…Olmesartan, but Not TSA, Attenuated ISO-induced Cardiac Hypertrophy in CM Klf4 KO Mice-Both angiotensin II type 1 receptor antagonists (16,17) and histone deacetylase inhibitors (18,28) have been shown to attenuate the progression of cardiac hypertrophy. We determined whether the antihypertrophic effects of olmesartan and TSA were mediated by KLF4 using CM Klf4 KO mice.…”

Emerging Roles for Histone Deacetylases in Pulmonary Hypertension and Right Ventricular Remodeling (2013 Grover Conference series)

“…60 Similarly, TSA and VPA suppressed LV hypertrophy induced by infusion of angiotensin II or pressure-overload due to transverse aortic constriction. 61 TSA treatment was also shown to regress established LV hypertrophy in mice subjected to aortic constriction, 61 and it reversed established atrial fibrosis in Hop-transgenic mice, 62 suggesting potential for HDAC inhibitors for the treatment of preexisting LV failure. Consistent with this, Hill and colleagues convincingly demonstrated that TSA reverses established LV hypertrophy in Beclin 1 transgenic mice subjected to pressure overload.…”