| Autor: |
Eaton, Deborah M., Lee, Benjamin W., Caporizzo, Matthew A., Iyengar, Amit, Chen, Christina Y., Uchida, Keita, Marcellin, Guillaume, Lannay, Yoann, Vite, Alexia, Bedi Jr., Kenneth C., Brady, Claire F., Smolyak, Julia N., Meldrum, Danika, Dominic, Jessica, Weingarten, Noah, Patel, Mrinal, Belec, Andrew, Hached, Khaled, Atluri, Pavan, Van Der Laan, Siem |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 7/17/2024, Vol. 16 Issue 756, p1-13, 13p |
| Abstrakt: |
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. Editor's summary: Heart failure with preserved ejection fraction (HFpEF) is a growing clinical concern with limited pharmacological options for treatment. HFpEF is characterized by reduced ability of the myocardium to relax properly during diastole. Eaton, Lee, and Caporizzo et al. developed and tested two vasohibin inhibitors that decreased α-tubulin detyrosination to improve cardiomyocyte relaxation. In a ZSF1 obese rat model of HFpEF, isolated cardiomyocytes had increased relaxation and decreased stiffness after vasohibin inhibition compared with cardiomyocytes from lean rats. In vivo vasohibin inhibition improved diastolic relaxation in these rat hearts. In cells from human hearts with or without heart failure, vasohibin inhibition resulted in improved relaxation in vitro. These results suggest that inhibiting detyrosination of microtubule networks in cardiomyocytes could be a target for treating HFpEF. —Brandon Berry [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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