Inhibition of Mammalian Sterile 20‐like Kinase 1 Rescues Cardiomyopathy through Protection from Myocyte Necrosis as well as Apoptosis (LB700)

Abstract

Inhibition of Mammalian Sterile 20‐like Kinase 1 (MST1) is known to have cardioprotective effects by preventing myocyte apoptosis. We examined the effects of MST1 inhibition in β1‐adrenergic receptor (β1‐AR) cardiomyopathy by mating dominant negative (DN)‐MST1 mice with β1‐AR mice. As the mice aged, the bigenic mice had higher left ventricular ejection fraction (67+12% vs 43+5%) and decreased cardiac fibrosis (8.8+1.5% vs 19.5+2.7%). It is generally believed that fibrosis in cardiomyopathy is secondary to necrosis, more than apoptosis. Accordingly, we hypothesized that MST1 may also mediate necrosis. We examined necrosis through in‐vivo labeling by Evans Blue Dye in DN‐MST1 mice after continuous isoproterenol (ISO) challenge. At 1 day after ISO the wild type hearts showed massive myocyte necrotic death (0.90+0.37%), which was significantly protected in DN‐MST1 (0.32+0.14% p<0.05), while having no discernible differences in myocyte apoptosis (0.10+0.03% vs 0.08+0.01%). These results suggest that MST1 may also have an important role in myocyte necrosis as well as apoptosis.