Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease (Mar 2024)

Myosin Light Chain Phosphatase Plays an Important Role in Cardiac Fibrosis in a Model of Mineralocorticoid Receptor‐Associated Hypertension

  • Zhe Ye,
  • Ryuji Okamoto,
  • Hiromasa Ito,
  • Rie Ito,
  • Keishi Moriwaki,
  • Mizuki Ichikawa,
  • Lupiya Kimena,
  • Yusuf Ali,
  • Masaaki Ito,
  • Celso E. Gomez‐Sanchez,
  • Kaoru Dohi

DOI
https://doi.org/10.1161/JAHA.123.032828
Journal volume & issue
Vol. 13, no. 5

Abstract

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Background Myosin phosphatase targeting subunit 2 (MYPT2) is an important subunit of cardiac MLC (myosin light chain) phosphatase, which plays a crucial role in regulating the phosphorylation of MLC to phospho‐MLC (p‐MLC). A recent study demonstrated mineralocorticoid receptor‐related hypertension is associated with RhoA/Rho‐associated kinase/MYPT1 signaling upregulation in smooth muscle cells. Our purpose is to investigate the effect of MYPT2 on cardiac function and fibrosis in mineralocorticoid receptor‐related hypertension. Methods and Results HL‐1 murine cardiomyocytes were incubated with different concentrations or durations of aldosterone. After 24‐hour stimulation, aldosterone increased CTGF (connective tissue growth factor) and MYPT2 and decreased p‐MLC in a dose‐dependent manner. MYPT2 knockdown decreased CTGF. Cardiac‐specific MYPT2‐knockout (c‐MYPT2−/−) mice exhibited decreased type 1 phosphatase catalytic subunit β and increased p‐MLC. A disease model of mouse was induced by subcutaneous aldosterone and 8% NaCl food for 4 weeks after uninephrectomy. Blood pressure elevation and left ventricular hypertrophy were observed in both c‐MYPT2−/− and MYPT2+/+ mice, with no difference in heart weights or nuclear localization of mineralocorticoid receptor in cardiomyocytes. However, c‐MYPT2−/− mice had higher ejection fraction and fractional shortening on echocardiography after aldosterone treatment. Histopathology revealed less fibrosis, reduced CTGF, and increased p‐MLC in c‐MYPT2−/− mice. Basal global radial strain and global longitudinal strain were higher in c‐MYPT2−/− than in MYPT2+/+ mice. After aldosterone treatment, both global radial strain and global longitudinal strain remained higher in c‐MYPT2−/− mice compared with MYPT2+/+ mice. Conclusions Cardiac‐specific MYPT2 knockout leads to decreased myosin light chain phosphatase and increased p‐MLC. MYPT2 deletion prevented cardiac fibrosis and dysfunction in a model of mineralocorticoid receptor‐associated hypertension.

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