Late-Breaking Science

Abstract

### H11 Kinase Promotes or Inhibits Cardiac Cell Growth and Survival, Depending on its Subcellular Distribution Christophe Depre, Anna Zajac, Nadia Hedhli, Chull Hong, Jing Liu, Guiping Yang, Li Wang, Huacheng Dai, Univ. Medicine New Jersey, Newark, NJ; Thomas Wagner, Greenville Hosp System, Greenville, SC; Stephen F Vatner; Univ. Medicine New Jersey, Newark, NJ H11 kinase is a protein of unknown function mainly expressed in heart and skeletal muscle. Its expression is markedly increased in the ischemic heart together with an array of cytoprotective and anti-apoptotic genes, which supposes that H11 kinase promotes cell survival. Paradoxically, overexpression of H11 kinase in other cell types induces apoptosis. Therefore, the goal of the present study was to determine how H11 kinase affects cardiac cell survival and death, using both a cardiac-specific transgenic (TG) mouse model and cardiac cell culture. After 45 min coronary occlusion in vivo, infarct size in hearts from TG mice (7-fold overexpression) was reduced by 80% compared to wild type (P<0.01). This protection was related to a significant (P<0.05) increase in the expression of proteins promoting cell survival, including heat-shock proteins (HSP70, mmDJA4), phospho-Akt, the mTOR targets p70S6K and 4EBP-1, and the glucose transporter GLUT1. Surprisingly, although overexpression of H11 kinase is protective in the TG animal, ischemia reduced H11 kinase expression by 60% in wild type mice (P<0.01 versus sham). To reconcile this paradox, we performed a subcellular fractionation, which revealed that H11 kinase is expressed in both the cytosol and the nucleus. In wild type mice, the cytosolic expression of H11 kinase during ischemia was reduced by more than 80%, whereas the nuclear expression was unaffected. In the TG mouse, overexpression of H11 kinase accumulated as a nuclear protein, which therefore mediates the survival effect. To understand the role of the cytosolic form of the protein, we transfected isolated cardiac myocytes with increasing doses of adenovirus (3 MOI to 100 MOI) harboring the …