Dysregulation of H11 Kinase in the Failing Human Left Ventricular Myocardium
Gupta RC, Singh-Gupta V, and Sabbah HN. Dysregulation of H11 Kinase in the Failing Human Left Ventricular Myocardium. Journal of Heart and Lung Transplantation 2020; 39(4):S357.
J Heart Lung Transplant
Purpose: Mitochondrial dysfunction and ongoing cardiomyocyte loss from apoptosis contribute to the progressive LV dysfunction characteristic of the heart failure (HF) state. H11 kinase (H11K) is a 22-kD serine/threonine kinase protein abundantly expressed in the heart. Dysregulation of H11K occurs in HF but its potential contribution to the progression of HF is not fully understood. Cardiac deletion of H11K in mice with LV pressure overload has been shown to result in LV dilation, reduced hypertrophy, impaired contractile function, increased interstitial fibrosis and faster transition to HF. In this study, we examined the expression of H11K in LV myocardium and separately in cytosolic and mitochondrial fractions of explanted failing human hearts. Methods: Sodium-dodecyl sulfate (SDS) extracts were prepared from LV tissue of 7 explanted failed human hearts due to idiopathic dilated cardiomyopathy (IDC), 7 due to ischemic cardiomyopathy (ICM) and of 7 non-failing human donor hearts (DNR). Western blotting and specific antibodies were used to assess protein levels of H11K normalized to the internal control GAPDH in homogenate and cytosolic fractions and protein levels of H11K normalized to the internal control porin in mitochondrial fractions. Results: There were no differences in GAPDH and porin among the 3 groups. H11K protein levels were significantly increased in LV homogenate and cytosolic fractions but significantly decreased in mitochondrial fractions of both IDC and ICM failed human hearts compared to DNR hearts (Table). Conclusion: The failing human LV manifests increased H11K protein levels independent of HF etiology. The reduced H11K protein level in mitochondria and its increase in the cytosolic compartment of failing cardiomyocytes represents an adverse maladaptation capable of reducing ATP synthesis by mitochondria and activation of cardiomyocyte pro-apoptotic cell death pathways in the cytosol respectively thus likely contributing to the progression of HF.