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HDACs (Histone Deacetylases) have been identified as central regulators of mal-adaptive hypertrophy. HDAC6 enzymatic activity is strongly upregulated in different models of pressure-induced cardiac hypertrophy. Given the importance of HDACs, and in particular HDAC6- in the development of mal-adaptive hypertrophy and the pharmacological effect, a HDAC6 specific inhibitor (HDACi) Tubacin and a general HDACi Trichostatin A (TSA) were investigated in vitro and in vivo. In vitro we tested the pharmacological effects of both inhibitors TSA and Tubacin in murine HL-1 cardiomyocytes to identify the activity of HDAC6 under hypertrophic response. The hypertrophic response of HL-1 cardiomyocytes to Endothelin 1 (ET-1) stimulation led to the induction of mRNA expression of pathological marker atrial natriuretic factor (ANF), brain natriuretic peptide (BNP) und beta-myosin heavy chain (b-MHCH). Treatment with Tubacin and TSA significantly reduced the hypertrophic effect of ET-1 (ANF: ET-1 3.21±0.22; ET-1+TSA: 1.67±0.06; ET-1+Tub 1.69±0.48; P<0.05 vs. Et-1; b-MHCH: ET-1 3.2±0.21; ET-1+TSA 1.32±0.27; ET-1 + Tub 1.074±0.28; P<0.05 vs. ET-1). Furthermore we performed an in vivo experiment with C57Bl/6 male mice to identify the functional importance, the cardiac expression and the pharmacological inhibition of HDAC6 in the development of cardiac hypertrophy by using the HDAC6 specific inhibitor Tubacin, and unspecific HDAC inhibitor TSA in transverse aortic constriction (TAC)-model in mice, with an emphasis on cardiac glucose and fatty acid metabolism.
Treatment with both HDAC inhibitors TSA and Tubacin reduced the cardiac hypertrophic response in TAC operated mice. Both diastolic IVS and LVPW values were attenuated in the TSA- and Tubacin–treated mice. Key hypertrophic markers (ANF and BNP) significantly increased in vehicle-treated TAC mice. Treatment with TSA and Tubacin reduced the expression of both markers significantly. In summary, this study demonstrates for the first time that treatment with the selective HDAC6 inhibitor Tubacin significantly reduces cardiac hypertrophic responses in a model of pressure overload in mice. Although the underlying mechanism remains elusive, beneficial anti-hypertrophic effects of Tubacin are most probably not mediated by the metabolic modulation of cardiac tissue homeostasis.
HDAC6 specific inhibitors might be promising pharmacological tools to prevent mal-adaptive hypertrophy in the future.