Journal
BASIC RESEARCH IN CARDIOLOGY
Volume 110, Issue 2, Pages -Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00395-015-0461-1
Keywords
beta-Adrenergic receptor; Mammalian sterile 20-like kinase 1; Cardiomyopathy; Apoptosis; Necrosis
Categories
Funding
- NHLBI NIH HHS [R01 HL033107, R01 HL095888, R21 HL097264, R01 HL091781, R01 HL093481, T32 HL069752, R01 HL119464, R01 HL102472, R01 HL106511] Funding Source: Medline
- NIA NIH HHS [P01 AG027211] Funding Source: Medline
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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 beta(1)-adrenergic receptor (beta(1)-AR) stimulation by preventing myocyte apoptosis. DN-Mst1 mice were mated with beta(1)-AR transgenic (Tg) mice and followed for 20 months. beta(1)-AR Tg mice developed cardiomyopathy as they aged, as reflected by premature mortality and depressed cardiac function, which were rescued in beta(1)-AR x 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 beta-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 beta(1)-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.
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