TY - JOUR
T1 - Geranylgeranylacetone reduces cardiomyocyte stiffness and attenuates diastolic dysfunction in a rat model of cardiometabolic syndrome
AU - Waddingham, Mark T.
AU - Sequeira, Vasco
AU - Kuster, Diederik W. D.
AU - Dal Canto, Elisa
AU - Handoko, M. Louis
AU - de Man, Frances S.
AU - da Silva Gonçalves Bós, Denielli
AU - Ottenheijm, Coen A.
AU - Shen, Shengyi
AU - van der Pijl, Robbert J.
AU - van der Velden, Jolanda
AU - Paulus, Walter J.
AU - Eringa, Etto C.
N1 - Funding Information: This study was supported by grants from CardioVasculair Onderzoek Nederland (CVON), Dutch Heart Foundation, The Hague, The Netherlands (RECONNECT, EARLY‐HFpEF). Dr. Waddingham was a recipient of a Young Talent Program “Proof‐of‐Concept” Award from the CVON‐RECONNECT consortium of the Dutch Heart Foundation and is currently supported by a JSPS KAKENHI (Grant no. 22K15368). Publisher Copyright: © 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.
PY - 2023/11/1
Y1 - 2023/11/1
N2 - 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 (Fpassive) was determined by force measurements in relaxing solution with 100 nM [Ca2+] 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.
AB - 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 (Fpassive) was determined by force measurements in relaxing solution with 100 nM [Ca2+] 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.
KW - cardiomyocyte
KW - diastolic heart failure
KW - ejection fraction
KW - myofilament protein
KW - small heat shock proteins
UR - http://www.scopus.com/inward/record.url?scp=85177421631&partnerID=8YFLogxK
U2 - https://doi.org/10.14814/phy2.15788
DO - https://doi.org/10.14814/phy2.15788
M3 - Article
C2 - 37985159
SN - 2051-817X
VL - 11
JO - Physiological reports
JF - Physiological reports
IS - 22
M1 - e15788
ER -