Journal Article

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

Nagata, Kohzo, Ohno, Kinji, Obinata, Hideru, Hirayama, Masaaki, Yokoyama, Tomoyuki, Matsui, Hiroki, Kurabayashi, Masahiko, Furukawa, Nozomi, Sunaga, Hiroaki, Koitabashi, Norimichi

2024

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 692/163/2743 / 692/4017 / 692/4019 / 692/4019/592 / Aminobutyrates - pharmacology / Angiotensin / Angiotensin Receptor Antagonists - pharmacology / Animals / Biphenyl Compounds - pharmacology / Biphenyl Compounds - therapeutic use / Cardiomyopathy / Congestive heart failure / Connectin / Connectin - metabolism / Cyclic GMP / Cyclic GMP - metabolism / Cyclic GMP-Dependent Protein Kinases - metabolism / Diabetes / Diabetes mellitus / Diabetes Mellitus, Experimental - drug therapy / Diabetes Mellitus, Experimental - metabolism / Diabetes Mellitus, Experimental - physiopathology / Diabetic Cardiomyopathies - drug therapy / Diabetic Cardiomyopathies - metabolism / Diabetic Cardiomyopathies - physiopathology / Diastole - drug effects / Diastolic dysfunction / Drug Combinations / Heart failure / Heart Ventricles - drug effects / Heart Ventricles - metabolism / Heart Ventricles - physiopathology / HFpEF / Humanities and Social Sciences / Male / Medical instruments / Mice / Mice, Inbred C57BL / multidisciplinary / Myocardial stiffness / Neprilysin / Phosphorylation / Phosphorylation - drug effects / Protein Kinases / Science / Science (multidisciplinary) / Therapeutic targets / Titin / Valsartan - pharmacology / Ventricle / Ventricular Dysfunction, Left - drug therapy / Ventricular Dysfunction, Left - etiology / Ventricular Dysfunction, Left - metabolism