P283The Mammalian Ste20-like kinase 2 (Mst2) modulates pathological hypertrophy by regulating the Raf1-ERK1/2 signalling pathway

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Abstract

The mammalian STE20-like kinase 2 (Mst2) is a key component of the Hippo signalling pathway that is implicated in organ size control and tumour suppression. Recently, inactivation of components of the Hippo pathway has been associated with increased cardiomyocyte proliferation during embryonic development (Science 2011; 332:458-61). However, the role of Mst2 in adult heart, particularly in pathological conditions, is not known.

We analysed mice with genetic ablation of Mst2 gene. Mst2-/- mice exhibited a significant reduction of hypertrophy in response to transverse aortic constriction (30% elevation in heart weight/tibia length ratio in Mst2-/- mice compared to 50% in wild type, n=8, P < 0.05). This was accompanied by a significant reduction of cardiac fibrosis as well as lower expression of hypertrophic markers (BNP and ANP) in Mst2-/- mice. In agreement with the in vivo data, overexpression of Mst2 in neonatal rat cardiomyocytes significantly enhanced phenylephrine-induced cellular hypertrophy as indicated by cell size measurements and expression of the hypertrophic marker BNP. Moreover, overexpression of Mst2 in isolated cardiac fibroblast enhanced the expression of genes involved in fibrogenesis such as TGFβ1,TGFβ2 and TNFα. Mechanistically, we found that Mst2 interacted with Raf1 and activated the pro-hypertrophic Raf1-ERK1/2 pathway in both cardiomyocytes and cardiac fibroblasts. Mutation in the kinase domain of Mst2 (K56R mutation) abolished the ability to activate Raf1-ERK1/2 pathway. We also studied the potential involvement of Mst2 in human cardiac disease by screening single nucleotide polymorphisms (SNPs) within the Mst2 gene in patients with mitral valve prolapse (MVP). We found that a polymorphism in the 3'UTR region ( + 214G/A) of this gene was associated with profound left ventricular remodelling in MVP patients: patients with homozygous G allele had larger LVmass than patients with GA or AA allele (n=62, P < 0.05). This SNP is located at the predicted binding sites of human micro RNAs (miR-4773 and miR-1185), and hence may affect the level of Mst2 expression.

In conclusion, our data provides key evidence of a novel role of Mst2 as a positive regulator of cardiac hypertrophy and fibrosis by modulating the Raf1-ERK1/2 pathway. It also shows that Mst2 may play a major role in left ventricular remodelling in human heart disease, thereby revealing a potentially new therapeutic target.

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