Vasohibin inhibition improves myocardial relaxation in a rat model of heart failure with preserved ejection fraction.
Publication/Presentation Date
7-17-2024
Abstract
Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome associated with increased myocardial stiffness and cardiac filling abnormalities. Prior studies implicated increased α-tubulin detyrosination, which is catalyzed by the vasohibin enzymes, as a contributor to increased stabilization of the cardiomyocyte microtubule network (MTN) and stiffness in failing human hearts. We explored whether increased MTN detyrosination contributed to impaired diastolic function in the ZSF1 obese rat model of HFpEF and designed a small-molecule vasohibin inhibitor to ablate MTN detyrosination in vivo. Compared with ZSF1 lean and Wistar Kyoto rats, obese rats exhibited increased tubulin detyrosination concomitant with diastolic dysfunction, left atrial enlargement, and cardiac hypertrophy with a preserved left ventricle ejection fraction, consistent with an HFpEF phenotype. Ex vivo myocardial phenotyping assessed cardiomyocyte mechanics and contractility. Vasohibin inhibitor treatment of isolated cardiomyocytes from obese rats resulted in reduced stiffness and faster relaxation. Acute in vivo treatment with vasohibin inhibitor improved diastolic relaxation in ZSF1 obese rats compared with ZSF1 lean and Wistar Kyoto rats. Vasohibin inhibition also improved relaxation in isolated human cardiomyocytes from both failing and nonfailing hearts. Our data suggest the therapeutic potential for vasohibin inhibition to reduce myocardial stiffness and improve relaxation in HFpEF.
Volume
16
Issue
756
First Page
8842
Last Page
8842
ISSN
1946-6242
Published In/Presented At
Eaton, D. M., Lee, B. W., Caporizzo, M. A., Iyengar, A., Chen, C. Y., Uchida, K., Marcellin, G., Lannay, Y., Vite, A., Bedi, K. C., Jr, Brady, C. F., Smolyak, J. N., Meldrum, D., Dominic, J., Weingarten, N., Patel, M., Belec, A., Hached, K., Atluri, P., Van Der Laan, S., … Margulies, K. B. (2024). Vasohibin inhibition improves myocardial relaxation in a rat model of heart failure with preserved ejection fraction. Science translational medicine, 16(756), eadm8842. https://doi.org/10.1126/scitranslmed.adm8842
Disciplines
Medicine and Health Sciences
PubMedID
39018366
Department(s)
Department of Surgery
Document Type
Article