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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.

BACKGROUND

METHODS AND RESULTS

CONCLUSIONS

背景

肌球蛋白磷酸酶靶向亚单位 2（MYPT2）是心肌肌球蛋白轻链（MLC）磷酸酶的重要亚单位，在调节 MLC 的磷酸化以形成磷酸化-MLC（p-MLC）方面发挥着关键作用。最近的一项研究表明，醛固酮受体相关的高血压与血管平滑肌细胞中 RhoA/Rho 相关激酶/MYPT1 信号的上调有关。我们的目的是研究 MYPT2 对醛固酮受体相关高血压中心脏功能和纤维化的影响。

方法和结果

HL-1 鼠心肌细胞用不同浓度或时间的醛固酮孵育。经过 24 小时的刺激，醛固酮呈剂量依赖性地增加 CTGF（结缔组织生长因子）和 MYPT2，并降低 p-MLC。MYPT2 敲低降低了 CTGF。心脏特异性 MYPT2 敲除（c-MYPT2）小鼠表现出降低的 1 型磷酸酶催化亚基β和增加的 p-MLC。在单侧肾切除术后 4 周，通过皮下给予醛固酮和 8%NaCl 食物诱导小鼠疾病模型。在 c-MYPT2 和 MYPT2 小鼠中均观察到血压升高和左心室肥厚，但心肌细胞中的心脏重量或醛固酮受体核定位无差异。然而，在醛固酮治疗后，c-MYPT2 小鼠的射血分数和缩短分数更高。组织病理学显示 c-MYPT2 小鼠的纤维化程度更低，CTGF 减少，p-MLC 增加。c-MYPT2 小鼠的基础整体径向应变和整体纵向应变均高于 MYPT2 小鼠。在醛固酮治疗后，与 MYPT2 小鼠相比，c-MYPT2 小鼠的整体径向应变和整体纵向应变仍然更高。