Sacubitril/valsartan improves diastolic left ventricular stiffness with increased titin phosphorylation via cGMP-PKG activation in diabetic mice.

Autor: Furukawa N; Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.; Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, 3-39-22, Showa-Machi, Maebashi, Gunma, 371-8511, Japan.; Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan., Matsui H; Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Maebashi, Japan., Sunaga H; Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, 3-39-22, Showa-Machi, Maebashi, Gunma, 371-8511, Japan.; Center for Liberal Arts and Sciences, Ashikaga University, Ashikaga, Japan., Nagata K; Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan., Hirayama M; Department of Occupational Therapy, Chubu University College of Life and Health Sciences, Kasugai, Japan., Obinata H; Education and Research Support Center, Gunma University Graduate School of Medicine, Maebashi, Japan., Yokoyama T; Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Maebashi, Japan., Ohno K; Graduate School of Nutritional Sciences, Nagoya University of Arts and Sciences, Nisshin, Japan.; Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan., Kurabayashi M; Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, 3-39-22, Showa-Machi, Maebashi, Gunma, 371-8511, Japan., Koitabashi N; Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, 3-39-22, Showa-Machi, Maebashi, Gunma, 371-8511, Japan. koitabas@gunma-u.ac.jp.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Oct 23; Vol. 14 (1), pp. 25081. Date of Electronic Publication: 2024 Oct 23.
DOI: 10.1038/s41598-024-75757-8
Abstrakt: Titin, a giant sarcomeric protein, regulates diastolic left ventricular (LV) passive stiffness as a molecular spring and could be a therapeutic target for diastolic dysfunction. Sacubitril/valsartan (Sac/Val), an angiotensin receptor neprilysin inhibitor, has been shown to benefit patients with heart failure with preserved ejection fraction. The effect of Sac/Val is thought to be due to the enhancement of the cGMP/PKG pathway via natriuretic peptide. In this study, the effects of Sac/Val on LV diastolic dysfunction are demonstrated in a mouse diabetic cardiomyopathy model focusing on titin phosphorylation. Sac/Val-treated diabetic mice showed a greater increase in myocardial levels of cGMP-PKG than Val-treated and control mice. Conductance catheter analysis showed a significant reduction in LV stiffness in diabetic mice, but not in non-diabetic mice. Notably, diastolic LV stiffness was significantly reduced in Sac/Val-treated diabetic hearts compared with Val-treated or vehicle-treated diabetic mice. The phosphorylation level of titin (N2B), which determines passive stiffness and modulates active contraction, was higher in Sac/Val-treated hearts compared with Val-treated hearts in diabetic mice. Given that alteration of titin phosphorylation through PKG contributes to myocardial stiffness, the beneficial effects of Sac/Val in heart failure might be partly attributed to the induction of titin phosphorylation.
(© 2024. The Author(s).)
Databáze: MEDLINE
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