Selected Publication:

SHR Neuro Cancer Cardio Lipid Metab Microb

Eaton, DM; Martin, TG; Kasa, M; Djalinac, N; Ljubojevic-Holzer, S; Von, Lewinski, D; Pöttler, M; Kampaengsri, T; Krumphuber, A; Scharer, K; Maechler, H; Zirlik, A; McKinsey, TA; Kirk, JA; Houser, SR; Rainer, PP; Wallner, M.
HDAC Inhibition Regulates Cardiac Function by Increasing Myofilament Calcium Sensitivity and Decreasing Diastolic Tension.
Pharmaceutics. 2022; 14(7): Doi: 10.3390/pharmaceutics14071509 [OPEN ACCESS]
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Leading authors Med Uni Graz

Wallner Markus

Co-authors Med Uni Graz

Dalinac Natasa

Holzer Senka

Kasa Michael

Krumphuber Andreas

Mächler Heinrich

Rainer Peter

von Lewinski Dirk

Zirlik Andreas

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Abstract:

We recently established a large animal model that recapitulates key clinical features of heart failure with preserved ejection fraction (HFpEF) and tested the effects of the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). SAHA reversed and prevented the development of cardiopulmonary impairment. This study evaluated the effects of SAHA at the level of cardiomyocyte and contractile protein function to understand how it modulates cardiac function. Both isolated adult feline ventricular cardiomyocytes (AFVM) and left ventricle (LV) trabeculae isolated from non-failing donors were treated with SAHA or vehicle before recording functional data. Skinned myocytes were isolated from AFVM and human trabeculae to assess myofilament function. SAHA-treated AFVM had increased contractility and improved relaxation kinetics but no difference in peak calcium transients, with increased calcium sensitivity and decreased passive stiffness of myofilaments. Mass spectrometry analysis revealed increased acetylation of the myosin regulatory light chain with SAHA treatment. SAHA-treated human trabeculae had decreased diastolic tension and increased developed force. Myofilaments isolated from human trabeculae had increased calcium sensitivity and decreased passive stiffness. These findings suggest that SAHA has an important role in the direct control of cardiac function at the level of the cardiomyocyte and myofilament by increasing myofilament calcium sensitivity and reducing diastolic tension.

Find related publications in this database (Keywords)

heart failure

contractility

calcium

cardiomyocyte

myofilament

HDAC inhibitor

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