HDAC6 modulates myofibril stiffness and diastolic function of the heart

Research output: Contribution to journal › Journal article › Research › peer-review

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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

Harvard

Lin, Y-H, Major, JL, Liebner, T, Hourani, Z, Travers, JG, Wennersten, SA, Haefner, KR, Cavasin, MA, Wilson, CE, Jeong, MY, Han, Y, Gotthardt, M, Ferguson, SK, Ambardekar, AV, Lam, MP, Choudhary, C, Granzier, HL, Woulfe, KC & McKinsey, TA 2022, 'HDAC6 modulates myofibril stiffness and diastolic function of the heart', Journal of Clinical Investigation, vol. 132, no. 10, e148333. https://doi.org/10.1172/JCI148333

APA

Lin, Y-H., Major, J. L., Liebner, T., Hourani, Z., Travers, J. G., Wennersten, S. A., Haefner, K. R., Cavasin, M. A., Wilson, C. E., Jeong, M. Y., Han, Y., Gotthardt, M., Ferguson, S. K., Ambardekar, A. V., Lam, M. P., Choudhary, C., Granzier, H. L., Woulfe, K. C., & McKinsey, T. A. (2022). HDAC6 modulates myofibril stiffness and diastolic function of the heart. Journal of Clinical Investigation, 132(10), [e148333]. https://doi.org/10.1172/JCI148333

Vancouver

Lin Y-H, Major JL, Liebner T, Hourani Z, Travers JG, Wennersten SA et al. HDAC6 modulates myofibril stiffness and diastolic function of the heart. Journal of Clinical Investigation. 2022;132(10). e148333. https://doi.org/10.1172/JCI148333

Author

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. / HDAC6 modulates myofibril stiffness and diastolic function of the heart. In: Journal of Clinical Investigation. 2022 ; Vol. 132, No. 10.

Bibtex

@article{848eb8d2653c45d4a7ec424cfa3766e8,
title = "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.",
keywords = "Animals, Connectin/chemistry, Histone Deacetylase 6/genetics, Humans, Mice, Myocardium/metabolism, Myocytes, Cardiac/metabolism, Myofibrils/metabolism, Rats, Sarcomeres/metabolism",
author = "Ying-Hsi Lin and Major, {Jennifer L} and Tim Liebner and Zaynab Hourani and Travers, {Joshua G} and Wennersten, {Sara A} and Haefner, {Korey R} and Cavasin, {Maria A} and Wilson, {Cortney E} and Jeong, {Mark Y} and Yu Han and Michael Gotthardt and Ferguson, {Scott K} and Ambardekar, {Amrut V} and Lam, {Maggie Py} and Chunaram Choudhary and Granzier, {Henk L} and Woulfe, {Kathleen C} and McKinsey, {Timothy A}",
year = "2022",
doi = "10.1172/JCI148333",
language = "English",
volume = "132",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "American Society for Clinical Investigation",
number = "10",

}

RIS

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