Pro-survival effect of Dock180 overexpression on rat-derived H9C2 cardiomyocytes

Abstract

Background:Integrin b1 subunit and its downstream molecule, focal adhesion kinase (FAK), have been demonstrated to be indispensible to the promotion of cell proliferation and survival and anti-apoptosis in cardiomyocytes via activation of their downstream pro-survival signaling molecule, AKT. As a component of the integrin pathway, Dock180 (dedicator of cytokinesis 1) protein is also thought to be involved in the promotion of cell proliferation and survival and anti-apoptosis in the H9C2 cardiomyocytes. Material/Methods:Rat-derived H9C2 cardiomyocytes were transfected with pCXN2-flag-hDock180, a human Dock180 overexpression eukaryotic recombinant plasmid. The rat and human Dock180 mRNA and protein expression, apoptosis and cell proliferation and survival were analyzed in the H9C2 cardiomyocytes treated with either hypoxia/reoxygenation (H/R) or not, respectively. Results:Human Dock180 mRNA overexpression could significantly increase the Dock180 protein expression in the H9C2 cardiomyocytes, no matter whether treated with H/R or not. Dock180 overexpression could promote the cell proliferation and survival and anti-apoptosis, and relieve the cell proliferative and survival inhibition and apoptosis induced by H/R in the H9C2 cardiomyocytes via activation of its downstream pro-survival signaling molecule AKT. Conclusions: Dock180 could act as a pro-survival molecule in H9C2 cardiomyocytes via activation of its downstream prosurvival signaling molecule, AKT.key words: Dock180 apoptosis cell proliferation cardiomyocyte H9C2

Knockdown of CkrL by shRNA deteriorates hypoxia/reoxygenation‐induced H9C2 cardiomyocyte apoptosis and survival inhibition Via Bax and downregulation of P‐Erk1/2

“…[1][2][3] Increased apoptosis and cell survival inhibition in cardiomyocytes are the major causes of cardiomyocyte loss, ischemia/ reperfusion or H/R-induced myocardial injuries, postinfarction ventricular enlarged cardiomyopathy and systolic heart failure. [1][2][3] Increased apoptosis and cell survival inhibition in cardiomyocytes are the major causes of cardiomyocyte loss, ischemia/ reperfusion or H/R-induced myocardial injuries, postinfarction ventricular enlarged cardiomyopathy and systolic heart failure.…”

“…1,4,5 Targeting integrin pathway is a novel therapy measure for the previously mentioned cardiovascular diseases 6 because of its effects of cytoskeleton polymerisation and anti-apoptosis and prosurvival on the cardiomyocytes. 9 Integrin β1 subunit and its downstream molecules such as integrin-linked kinase (ILK), focal adhesion kinase (FAK), Dock180 (dedicator of cytokinesis 1) and C3G [v-crk avian sarcoma virus CT-10 oncogene homolog (Crk)-Src homology 3 (SH3) domain guanine nucleotide exchange factor] have been confirmed to be requisite to the inhibition of ischemia/reperfusion or H/R-induced myocardial injuries, postinfarction cardiac remodelling, ischemic cardiomyopathy and heart failure [10][11][12] because of their effects of actin cytoskeleton polymerisation and prosurvival and anti-apoptosis on the cardiomyocytes, 2,3,11,12 which are mediated possibly by regulating their downstream signalling molecules including Bax and phosphorylated extracellular signal-regulated kinase1/2 (p-ERK1/2). 9 Integrin β1 subunit and its downstream molecules such as integrin-linked kinase (ILK), focal adhesion kinase (FAK), Dock180 (dedicator of cytokinesis 1) and C3G [v-crk avian sarcoma virus CT-10 oncogene homolog (Crk)-Src homology 3 (SH3) domain guanine nucleotide exchange factor] have been confirmed to be requisite to the inhibition of ischemia/reperfusion or H/R-induced myocardial injuries, postinfarction cardiac remodelling, ischemic cardiomyopathy and heart failure [10][11][12] because of their effects of actin cytoskeleton polymerisation and prosurvival and anti-apoptosis on the cardiomyocytes, 2,3,11,12 which are mediated possibly by regulating their downstream signalling molecules including Bax and phosphorylated extracellular signal-regulated kinase1/2 (p-ERK1/2).…”

Enoxaparin Sensitizes Human Non–Small-Cell Lung Carcinomas to Gefitinib by Inhibiting DOCK1 Expression, Vimentin Phosphorylation, and Akt Activation

“…Interestingly, this downregulation of DOCK1 expression by enoxaparin 1 gefitinib is consistent with the downregulation of pAkt expression. In H9C2 cardiomyocytes, DOCK1 exerts its function via the activation of its downstream signaling molecule Akt (Dun et al, 2013;Yan et al, 2013). Therefore, we proved that enoxaparin substantially enhances the efficacy of gefitinib by inhibiting Akt activation via the suppression of DOCK1 expression.…”

“…DOCK proteins regulate the cytoskeleton, cell migration, and epithelial-to-mesenchymal transition (EMT). DOCK1 has been found to be important in tumor cell morphology, invasion, and migration (Cote and Vuori, 2007;Yan et al, 2013). Vimentin, a major constituent of the cytoskeleton intermediate filament (IF) family of proteins, plays an integral role in the progression of lung cancers, including cell morphology, invasion, migration, and EMT.…”

“…DOCK1 also regulates cytoskeleton polymerization (Cote and Vuori, 2007;Yan et al, 2013). Vimentin, a major constituent of the cytoskeleton IF family of proteins, plays an integral role in the progression of lung cancers, including cell migration and invasion, EMT, regulation of major signal transduction pathways, the positioning and anchorage of organelles, such as mitochondria, and cell-cell and cell-substrate adhesion (Tzivion et al 2000;Mendez et al, 2010;Kidd et al, 2014).…”