title: 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.
authors.affiliation: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, New Jersey Medical School, Rutgers University, 185 South Orange Avenue, MSB G609, Newark, NJ, 07103, USA.
authors.forename: Grace J
authors.initials: GJ
authors.lastname: Lee
authors.forename: Lin
authors.initials: L
authors.lastname: Yan
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Vatner
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Vatner
mesh_terms: D058665:Adrenergic beta-1 Receptor Agonists / Q000633:toxicity; D000818:Animals; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000378:metabolism*; D004195:Disease Models, Animal; D005355:Fibrosis / Q000473:pathology; D020287:In Situ Nick-End Labeling; D007545:Isoproterenol / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032342:Muscle Cells / Q000473:pathology*; D009206:Myocardium / Q000473:pathology*; D009336:Necrosis / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D000090742:Serine-Threonine Kinase 3; D000099317:Hippo Kinases
chemical_list: D058665:Adrenergic beta-1 Receptor Agonists; D007545:Isoproterenol; D017346:Protein Serine-Threonine Kinases; D018342:Receptors, Adrenergic, beta-1; D000090742:Serine-Threonine Kinase 3; C490818:Stk3 protein, mouse; D000099317:Hippo Kinases