Vasohibin inhibition improves myocardial relaxation in a rat model of heart failure with preserved ejection fraction.
Deborah M EatonBenjamin W LeeMatthew A CaporizzoAmit IyengarChristina Yingxian ChenKeita UchidaGuillaume MarcellinYoann LannayAlexia ViteKenneth C BediClaire F BradyJulia N SmolyakDanika MeldrumJessica DominicNoah WeingartenMrinal PatelAndrew BelecKhaled HachedPavan AtluriSiem Van Der LaanBenjamin L ProsserKenneth B MarguliesPublished in: Science translational medicine (2024)
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.
Keyphrases
- left ventricular
- ejection fraction
- left atrial
- aortic stenosis
- small molecule
- adipose tissue
- metabolic syndrome
- endothelial cells
- mitral valve
- weight loss
- type diabetes
- blood pressure
- single molecule
- heart failure
- obese patients
- atrial fibrillation
- angiotensin ii
- coronary artery disease
- high glucose
- induced pluripotent stem cells
- case report
- intensive care unit
- combination therapy
- coronary artery
- room temperature
- high throughput
- oxidative stress
- postmenopausal women
- respiratory failure
- pulmonary artery
- pluripotent stem cells
- congenital heart disease
- drug induced