Urotensin II induction of neonatal cardiomyocyte hypertrophy involves the CaMKII/PLN/SERCA 2a signaling pathway

• Published in: Gene 2016-05, Vol.583 (1), p.8-14
• Main Authors: Shi, Hongtao, Han, Qinghua, Xu, Jianrong, Liu, Wenyuan, Chu, Tingting, Zhao, Li
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Benzylamines - pharmacology; Calcium - metabolism; Calcium-Binding Proteins - metabolism; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - antagonists & inhibitors; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; CaMKII; Cardiomyocyte hypertrophy; Cell Size - drug effects; Cells, Cultured; Hypertrophy - chemically induced; Hypertrophy - pathology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Phosphorylation - drug effects; PLN; Rats, Sprague-Dawley; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism; SERCA 2a; Signal Transduction - drug effects; Sulfonamides - pharmacology; UII; Urotensins - toxicity
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2016.02.039

Although studies have shown that Urotensin II (UII) can induce cardiomyocyte hypertrophy and UII-induced cardiomyocyte hypertrophy model has been widely used for hypertrophy research, but its precise mechanism remains unknown. Recent researches have demonstrated that UII-induced cardiomyocyte hypertrophy has a relationship with the changes of intracellular Ca2+ concentration. Therefore, the aim of this study was to investigate the mechanisms of cardiomyocyte hypertrophy induced by UII and to explore whether the calcium/calmodulin-dependent protein kinase II (CaMKII)-mediated up-regulating of phospholamban (PLN) Thr17–phosphorylation signaling pathway contributed to UII-induced cardiomyocyte hypertrophy. Primary cultures of neonatal rat cardiomyocytes were stimulated for 48h with UII. Cell size, protein/DNA contents and intracellular Ca2+ were determined. Phosphorylated and total forms of CaMKII, PLN and the total amount of serco/endo-plasmic reticulum ATPases (SERCA 2a) were quantified by western blot. The responses of cardiomyocytes to UII were also evaluated after pretreatment with the CaMKII inhibitor, KN-93. These results showed that UII increased cell size, protein/DNA ratio and intracellular Ca2+, consistent with a hypertrophic response. Furthermore, the phosphorylation of CaMKII and its downstream target PLN (Thr17), SERCA 2a levels were up-regulated by UII treatment. Conversely, treatment with KN-93 reversed all those effects of UII. Taken together, the results suggest that UII can induce cardiomyocyte hypertrophy through CaMKII-mediated up-regulating of PLN Thr17–phosphorylation signaling pathway. •UII increases cardiomyocyte size, protein/DNA ratio and intracellular Ca2+, consistent with a hypertrophic response.•UII upregulates the phosphorylation of CaMKII and its downstream target PLN (Thr17), SERCA 2a levels.•UII induces cardiomyocyte hypertrophy through CaMKII-mediated up-regulating of PLN Thr17–phosphorylation signaling pathway.