HDAC6 modulates myofibril stiffness and diastolic function of the heart
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HDAC6 modulates myofibril stiffness and diastolic function of the heart. / Lin, Ying-Hsi; Major, Jennifer L; Liebner, Tim; Hourani, Zaynab; Travers, Joshua G; Wennersten, Sara A; Haefner, Korey R; Cavasin, Maria A; Wilson, Cortney E; Jeong, Mark Y; Han, Yu; Gotthardt, Michael; Ferguson, Scott K; Ambardekar, Amrut V; Lam, Maggie Py; Choudhary, Chunaram; Granzier, Henk L; Woulfe, Kathleen C; McKinsey, Timothy A.
In: Journal of Clinical Investigation, Vol. 132, No. 10, e148333, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - HDAC6 modulates myofibril stiffness and diastolic function of the heart
AU - Lin, Ying-Hsi
AU - Major, Jennifer L
AU - Liebner, Tim
AU - Hourani, Zaynab
AU - Travers, Joshua G
AU - Wennersten, Sara A
AU - Haefner, Korey R
AU - Cavasin, Maria A
AU - Wilson, Cortney E
AU - Jeong, Mark Y
AU - Han, Yu
AU - Gotthardt, Michael
AU - Ferguson, Scott K
AU - Ambardekar, Amrut V
AU - Lam, Maggie Py
AU - Choudhary, Chunaram
AU - Granzier, Henk L
AU - Woulfe, Kathleen C
AU - McKinsey, Timothy A
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - Animals
KW - Connectin/chemistry
KW - Histone Deacetylase 6/genetics
KW - Humans
KW - Mice
KW - Myocardium/metabolism
KW - Myocytes, Cardiac/metabolism
KW - Myofibrils/metabolism
KW - Rats
KW - Sarcomeres/metabolism
U2 - 10.1172/JCI148333
DO - 10.1172/JCI148333
M3 - Journal article
C2 - 35575093
VL - 132
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 10
M1 - e148333
ER -
ID: 310570517