Cardiac HDAC6 catalytic activity is induced in response to chronic hypertension

Area of Science:

• Cardiovascular Research
• Molecular Biology
• Biochemistry

Background:

• Small molecule histone deacetylase (HDAC) inhibitors show promise in animal models for treating heart failure by blocking adverse cardiac remodeling.
• While Class I and IIa HDACs have known roles in cardiac remodeling, the function of Class IIb HDACs in the heart remains largely unexplored.

Purpose of the Study:

• To investigate the role and regulation of different HDAC classes, particularly Class IIb HDACs, in the context of hypertensive heart disease.
• To determine the specific HDAC activity profiles in cardiac tissue under pathological and physiological conditions.

Main Methods:

• Development of assays to measure the catalytic activity of distinct HDAC classes in left and right ventricular cardiac tissue from animal models.
• Analysis of HDAC activity in animal models of hypertensive heart disease and physiological hypertrophy.
• Assessment of HDAC6 activity in response to extracellular stimuli in cultured cardiac cells (myocytes and fibroblasts).

Main Results:

• Class I and IIa HDAC activity showed variable increases in diseased cardiac tissues.
• Catalytic activity of the Class IIb HDAC, HDAC6, was consistently elevated in stressed myocardium, but not in physiological hypertrophy.
• HDAC6 activity was induced by various extracellular stimuli in cultured cardiac myocytes and fibroblasts, suggesting a specific role in cardiac stress responses.

Conclusions:

• HDAC6 exhibits an unexpected and consistent increase in activity in stressed heart muscle, differentiating it from other HDAC classes.
• These findings underscore the need for pre-clinical evaluation of HDAC6-selective inhibitors to ascertain its pathological or protective role in cardiovascular disease.
• The study highlights HDAC6 as a potential novel therapeutic target for heart failure and related cardiovascular conditions.