2. Academic Validation
  3. Vasohibin inhibition improves myocardial relaxation in a rat model of heart failure with preserved ejection fraction

Vasohibin inhibition improves myocardial relaxation in a rat model of heart failure with preserved ejection fraction

  • Sci Transl Med. 2024 Jul 17;16(756):eadm8842. doi: 10.1126/scitranslmed.adm8842.
Deborah M Eaton 1,  Benjamin W Lee 1,  Matthew A Caporizzo 2 3,  Amit Iyengar 4,  Christina Y Chen 2,  Keita Uchida 2,  Guillaume Marcellin 5,  Yoann Lannay 5,  Alexia Vite 1,  Kenneth C Bedi Jr 1,  Claire F Brady 1,  Julia N Smolyak 1,  Danika Meldrum 4,  Jessica Dominic 4,  Noah Weingarten 4,  Mrinal Patel 4,  Andrew Belec 4,  Khaled Hached 5,  Pavan Atluri 4,  Siem Van Der Laan 5,  Benjamin L Prosser 2,  Kenneth B Margulies 1
Affiliations

Affiliations

  • 1 Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 2 Department of Physiology and Pennsylvania Muscle Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 3 Department of Molecular Physiology and Biophysics, University of Vermont's Larner College of Medicine, Burlington, VT 05405, USA.
  • 4 Division of Cardiac Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 5 MT-act, CRBM, Montpellier 34396, France.
PMID: 39018366 DOI: 10.1126/scitranslmed.adm8842
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.

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