Abstract 11521: The Mammalian Ste20-like Kinase 2 (Mst2), a Key Regulator of the Hippo Pathway, Modulates Cardiac Hypertrophy and Remodeling
The Hippo signaling pathway has recently moved to center stage in cardiac research because of its key role in cardiomyocyte proliferation and regeneration of the embryonic and newborn heart. However, its role in remodeling of the adult heart is less clear. We here investigate the role of Mammalian Ste20-like kinase 2 (Mst2), one of the two mammalian orthologs of Drosophila hippo, the central regulator of this pathway. Mice with genetic ablation of Mst2 gene (Mst2-/-) exhibited a significant reduction of hypertrophy in response to transverse aortic constriction (TAC): heart weight/tibia length ratio after 2 weeks TAC: Mst2-/-, 7.32 mg/mm vs wild type (WT), 8.35 mg/mm, n=8, P<0.05. Mst2-/- mice showed a significant reduction of cardiac fibrosis, lower expression of hypertrophic markers (BNP and ANP) and better contractility (end systolic elastance) compared to WT following TAC. Consistently, Mst2-/- mice showed reduce hypertrophy and fibrosis following chronic infusion with Angiotensin II. Moreover, adenovirus mediated overexpression of Mst2 in neonatal rat cardiomyocytes significantly enhanced phenylephrine-induced cellular hypertrophy as indicated by cell size measurement and BNP expression. Mechanistically, we found that Mst2 interacted with Raf1 and activated the pro-hypertrophic Raf1-ERK1/2 pathway in cardiomyocytes. Mutation in the kinase domain of Mst2 (K56R mutation) abolished the ability to activate Raf1-ERK1/2 pathway. However, activation of the canonical downstream effectors of the Hippo pathway (LATS and YAP) were not affected by Mst2 ablation. Clinical implication of this finding was revealed as our initial genetic study in mitral valve prolapse patients showed an association between a polymorphism in the human Mst2 gene (+214G/A) and adverse cardiac remodelling: patients with homozygous G allele had larger LVmass than patients with GA or AA allele (n=62, P<0.05). Using cellular model we found that the polymorphism in patients with higher remodeling (+214GG) directed higher gene expression. Overall , our results show a novel role of Mst2 in stress-dependent cardiac hypertrophy and remodeling in the adult mouse and likely human heart, and hence revealing a potentially new therapeutic target.
- © 2012 by American Heart Association, Inc.