Geranylgeranylacetone reduces cardiomyocyte stiffness and attenuates diastolic dysfunction in a rat model of cardiometabolic syndrome.

Autor: Waddingham MT; Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Department of Cardiac Physiology, National Cerebral and Cardiovascular Center, Suita, Japan., Sequeira V; Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, The Netherlands., Kuster DWD; Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, The Netherlands., Dal Canto E; Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands., Handoko ML; Department of Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, The Netherlands., de Man FS; Department of Pulmonology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, The Netherlands., da Silva Gonçalves Bós D; Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, The Netherlands., Ottenheijm CA; Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona, USA., Shen S; Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona, USA., van der Pijl RJ; Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona, USA., van der Velden J; Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, The Netherlands., Paulus WJ; Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, The Netherlands., Eringa EC; Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
Jazyk: angličtina
Zdroj: Physiological reports [Physiol Rep] 2023 Nov; Vol. 11 (22), pp. e15788.
DOI: 10.14814/phy2.15788
Abstrakt: Titin-dependent stiffening of cardiomyocytes is a significant contributor to left ventricular (LV) diastolic dysfunction in heart failure with preserved LV ejection fraction (HFpEF). Small heat shock proteins (HSPs), such as HSPB5 and HSPB1, protect titin and administration of HSPB5 in vitro lowers cardiomyocyte stiffness in pressure-overload hypertrophy. In humans, oral treatment with geranylgeranylacetone (GGA) increases myocardial HSP expression, but the functional implications are unknown. Our objective was to investigate whether oral GGA treatment lowers cardiomyocyte stiffness and attenuates LV diastolic dysfunction in a rat model of the cardiometabolic syndrome. Twenty-one-week-old male lean (n = 10) and obese (n = 20) ZSF1 rats were studied, and obese rats were randomized to receive GGA (200 mg/kg/day) or vehicle by oral gavage for 4 weeks. Echocardiography and cardiac catheterization were performed before sacrifice at 25 weeks of age. Titin-based stiffness (F passive ) was determined by force measurements in relaxing solution with 100 nM [Ca 2+ ] in permeabilized cardiomyocytes at sarcomere lengths (SL) ranging from 1.8 to 2.4 μm. In obese ZSF1 rats, GGA reduced isovolumic relaxation time of the LV without affecting blood pressure, EF or LV weight. In cardiomyocytes, GGA increased myofilament-bound HSPB5 and HSPB1 expression. Vehicle-treated obese rats exhibited higher cardiomyocyte stiffness at all SLs compared to lean rats, while GGA reduced stiffness at SL 2.0 μm. In obese ZSF1 rats, oral GGA treatment improves cardiomyocyte stiffness by increasing myofilament-bound HSPB1 and HSPB5. GGA could represent a potential novel therapy for the early stage of diastolic dysfunction in the cardiometabolic syndrome.
(© 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)
Databáze: MEDLINE
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