Dysregulation of H11 Kinase in the Failing Left Ventricular Myocardium

Abstract

Background: Increased expression of H11 kinase (H11K) has been observed in Left Ventricular (LV) myocardium of failed human hearts. Its potential role as a contributor to the progression of Heart Failure (HF) remains uncertain. In the present study we examined the expression of H11K in cytosolic and mitochondrial fractions of failing human and dog LV myocardium and assessed its interaction with Akt (cell-survival enzyme) and p38MAPK (programmed cell death enzyme). Methods: Total RNA and Sodium-Dodecyl Sulfate (SDS) extracts were prepared from homogenate of LV specimens of 6 dogs with intracoronary microembolization-induced HF, 6 normal (NL) dogs, 7 explanted failed human hearts due to Idiopathic Dilated Cardiomyopathy (IDC), 7 failed human hearts due to Ischemic Cardiomyopathy (ICM) and 7 non-failing human donor hearts (DNR). SDS extracts were also prepared from cytosolic and mitochondrial fractions isolated from LV specimens. Results: H11K mRNA and protein levels normalized to GAPDH increased significantly in LV tissue from ICM and IDC hearts compared to DNR hearts and in HF dogs compared with NL dogs. H11K protein levels increased in cytosolic fractions but decreased in mitochondrial fractions of both failed human and dog hearts compared to DNR hearts and NL dog hearts. Immunoprecipitation studies in specimens from HF dogs showed that H11K cytosolic fractions interacted predominantly with p38MAPK and least with Akt when compared with NL dogs. Conclusions: Enhanced interaction of H11K with p38MAPK in HF can promote cell death thus contributing to progressive LV dysfunction. Therapeutic modalities that restore interaction of H11K with Akt and augment H11K translocation to mitochondria can potentially and partially reverse the progression of LV dysfunction by promoting cell survival.