Mst1 inhibition rescues β1-adrenergic cardiomyopathy by reducing myocyte necrosis and non-myocyte apoptosis rather than myocyte apoptosis

Abstract

It is generally held that inhibition of mammalian sterile 20-like kinase 1 (Mst1) protects the heart through reducing myocyte apoptosis. We determined whether inhibition with a dominant-negative Mst1 (DN-Mst1) would protect against the cardiomyopathy induced by chronic β1-adrenergic receptor (β1-AR) stimulation by preventing myocyte apoptosis. DN-Mst1 mice were mated with β1-AR transgenic (Tg) mice and followed for 20 months. β1-AR Tg mice developed cardiomyopathy as they aged, as reflected by premature mortality and depressed cardiac function, which were rescued in β1-AR × DN-Mst1 bigenic mice. Surprisingly, myocyte apoptosis did not significantly decrease with Mst1 inhibition. Instead, Mst1 inhibition predominantly reduced non-myocyte apoptosis, e.g., fibroblasts, macrophages, neutrophils and endothelial cells. Fibrosis in the hearts with cardiomyopathy increased fivefold and this increase was nearly abolished in the bigenic mice with Mst1 inhibition. Regression analysis showed no correlation between myocyte apoptosis and cardiac function or myocyte number, whereas the latter two correlated significantly, p < 0.05, with fibrosis, which generally results from necrosis. To examine the role of myocyte necrosis, chronic β-AR stimulation with isoproterenol was induced for 24 h and myocyte necrosis was assessed by 1 % Evans blue dye. Compared to WT, DN-Mst1 mice showed significant inhibition, p < 0.05, of myocyte necrosis. We confirmed this result in Mst1-knockout mice, which also showed significant protection, p < 0.05, against myocyte necrosis compared to WT. These data indicate that Mst1 inhibition rescued cardiac fibrosis and myocardial dysfunction in β1-AR cardiomyopathy. However, this did not occur through Mst1 inhibition of myocyte apoptosis but rather by inhibition of cardiomyocyte necrosis and non-myocyte apoptosis, features of Mst1 not considered previously.

Activation of melatonin receptor 2 but not melatonin receptor 1 mediates melatonin‐conferred cardioprotection against myocardial ischemia/reperfusion injury

“…Nonetheless, our current study for the first time provided the evidence that MT2 but not MT1 is a newly identified cardiac guardian receptor against MI/R injury. Besides, our current study failed to distinguish between myocyte and nonmyocyte apoptosis in the evaluation of cardiac apoptosis as established by previous reports, but the beneficial effects of melatonin in cardiac apoptosis inhibition might not be limited to cardiomyocytes according to previous studies . Additionally, as for the possible role and downstream signaling of MT1 in cardiomyocytes, this was a very interesting issue.…”

β‐Adrenoceptor activation affects galectin‐3 as a biomarker and therapeutic target in heart disease

“…Cardiac Mst1 is up‐regulated in experimental models of MI (Odashima et al, ), pathological hypertrophy (Odashima et al, ), arrhythmic cardiomyopathy (Chen et al, ), diabetic cardiomyopathy (Hu et al, ), or cardiomyopathy due to cardiac overexpression of β 1 ‐ or β 2 ‐adrenoceptors (Chen et al, ; Lee, Yan, Vatner, & Vatner, ; Peter et al, ; Zhao et al, ). In cardiac biopsy samples from patients with DCM or arrhythmogenic cardiomyopathy, and HF due to ischaemic cardiomyopathy or DCM, YAP phosphorylation at Ser 127 is increased implying activation of the Hippo signalling pathway (Chen et al, ; Hou et al, ; Leach et al, ).…”

“…Lee et al studied the effect of cardiomyocyte‐specific inactivation of Mst1 in the β 1 ‐TG cardiomyopathy model by crossing the β 1 ‐TG mice with dnMst1‐TG mice to generate dual TG mice and mice with control genotypes (Lee et al, ). They studied cardiac phenotype in animals at 18–20 months of age and revealed inhibition by approximately 60% of cardiomyocyte apoptosis and myocardial fibrosis together with improved LV function and survival (Lee et al, ). In Mst1 gene deleted mice, similar protection against cardiotoxicity by isoprenaline treatment (60 mg −1 ·kg −1 ·day −1 for 24 hr via minipump) was observed (Lee et al, ).…”

Signaling Pathways in Cardiac Myocyte Apoptosis

“…A possible explanation is that isoproterenol may promote cell survival or death in a dose-dependent fashion via activation of distinct pathways: treatment with low-dose isoproterenol enhances cell survival by increasing ERK1/2-mediated expression of Bcl-2, while stimulation with high concentration of isoproterenol leads to cell death through PKA-dependent downregulation of Bcl-2 [140]. Interestingly, chronic β 1-AR stimulation by transgenic expression of β 1-AR or by isoproterenol injection also resulted in necrotic myocyte death that is dependent on mammalian Ste20-like kinase 1 (Mst1) [151]. …”