HDAC6 modulates myofibril stiffness and diastolic function of the heart

Abstract

Passive stiffness of the heart is determined largely by extracellular matrix and titin, which functions as a molecular spring within sarcomeres. Titin stiffening is associated with the development of diastolic dysfunction (DD), while augmented titin compliance appears to impair systolic performance in dilated cardiomyopathy. We found that myofibril stiffness was elevated in mice lacking histone deacetylase 6 (HDAC6). Cultured adult murine ventricular myocytes treated with a selective HDAC6 inhibitor also exhibited increased myofibril stiffness. Conversely, HDAC6 overexpression in cardiomyocytes led to decreased myofibril stiffness, as did ex vivo treatment of mouse, rat, and human myofibrils with recombinant HDAC6. Modulation of myofibril stiffness by HDAC6 was dependent on 282 amino acids encompassing a portion of the PEVK element of titin. HDAC6 colocalized with Z-disks, and proteomics analysis suggested that HDAC6 functions as a sarcomeric protein deacetylase. Finally, increased myofibril stiffness in HDAC6-deficient mice was associated with exacerbated DD in response to hypertension or aging. These findings define a role for a deacetylase in the control of myofibril function and myocardial passive stiffness, suggest that reversible acetylation alters titin compliance, and reveal the potential of targeting HDAC6 to manipulate the elastic properties of the heart to treat cardiac diseases.

Augmentation of Histone Deacetylase 6 Activity Impairs Mitochondrial Respiratory Complex I in Ischemic/Reperfused Diabetic Hearts

“…Emerging evidence suggests that HDAC6 is profoundly implicated in the responses of the heart to MIRI, hypertension, angiotensin II, etc. 4, 14, 15 Collectively, HDAC6 is an essential negative regulator of MIRI in T1D.…”

“…Histone deacetylase (HDAC) 6 functions to remove acetyl groups of lysine residues from histone and nonhistone proteins. [3][4][5] HDAC6-reversible lysine acetylation was recently identified as a posttranslational modification that controls mitochondrial, myofibril, sarcomere, and microtubule functions and myocardial passive stiffness. 4,[6][7][8][9][10][11][12] The catalytic activity and expression of HDAC6 can be induced in response to hyperglycemic stress, MIRI, hypertension, and angiotensin II.…”

“…[3][4][5] HDAC6-reversible lysine acetylation was recently identified as a posttranslational modification that controls mitochondrial, myofibril, sarcomere, and microtubule functions and myocardial passive stiffness. 4,[6][7][8][9][10][11][12] The catalytic activity and expression of HDAC6 can be induced in response to hyperglycemic stress, MIRI, hypertension, and angiotensin II. [13][14][15] Importantly, pharmacological inhibition of HDAC6 confers cardioprotection in T1D rodents with acute myocardial infarction and diabetic cardiomyopathy.…”

Roles of histone acetylation sites in cardiac hypertrophy and heart failure

“…Phosphorylation of HDAC class IIa by phosphatases such as calcium/calmodulin-dependent protein kinase 2 prevents its binding to Mef2 and activates gene transcription ( 62 ). In addition, HDAC6 is involved in tubulin acetylation, myofibril stiffness and skeletal muscle wasting in cardiac disease ( 63 – 65 ). However, few reports on cardiac hypertrophy and heart failure associated with HDAC class IIb and IV are available, and he role of these HDACs in the heart needs to be clarified in the future.…”

Cardiac Acetylation in Metabolic Diseases

“…The comparison of lysine acetylation patterns from rats as well as from human skeletal muscle biopsies revealed that 80% of the proteins involved in muscle contraction were acetylated [ 9 ]. Moreover, proteomic analyses suggested that HDAC6 is localized in Z-disks and acts as a sarcomeric protein desacetylase [ 58 ]. Among them, acetylation can impact the β-myosin heavy chain (lysine 34, lysine 58, lysine 213, lysine 429, lysine 951 and lysine 1195) [ 31 ], titin [ 33 ], CapZβ1 (lysine 199) [ 34 ] or cardiac troponin I [ 35 ], directly affecting cardiac contraction.…”