Ca～(2+) /calmodulin-dependent Protein Kinaseⅱdirectly Mediates Angiotensin Ⅱ-induced Cardiac Remodeling

Objective: To explore whether Ca2+/calmodulin-dependent protein kinaseâ…¡(CaMKâ…¡) directly mediates angiotensinâ…¡(Angâ…¡)-induced myocardial hypertrophy and myofibrillogenesis in a mouse model.Methods: Twenty male C57BL/6J mice were randomly divided into Angâ…¡group and control group of 10 animals each. Mice were given daily intraperitoneal injection of the same dose (1.6 mg/ (kg.d)) of Angâ…¡in Angâ…¡group and distilled water in control group, respectively, for 3 weeks. Initial body weight, final heart and body weight as well as the heart-to-body weight ratio (HW/BW) were measured to estimate the degree of cardiac hypertrophy. We also observed the morphology change of cardiac myocyte with Hematoxylin-eosin staining and the myofibrillogenesis of heart tissue with Masson staining. Moreover, mRNA level of CaMKâ…¡was measured with Real-time quantitative polymerase chain reaction (real-time PCR), and the expression level and biological activity of CaMKâ…¡were detected by Western blot.Results: Intraperitoneal injection of Angâ…¡for three weeks in the mouse model was shown to increase the degree of cardiac hypertrophy (HW/BW), myofibrillogenesis (PVF/VA) and diameter of cardiac myocytes by 1.08 fold, 1.57 fold and 2.3 fold respectively (P<0.05 or 0.01) when compared with those mice with distilled water injection. Furthermore, all mice with Angâ…¡injection showed significant increase of both mRNA and protein expression level of cardiac CaMKâ…¡,with up to 1.53 and 2.03 times higher in the Angâ…¡group. Moreover, the phosphorylated activity of CaMK Angâ…¡reached 2.94-times-of-magnitude higher in the Angâ…¡group.Conclusion: Our findings indicate that intraperitoneal injection of AngII leads to cardiac hypertrophy and myofibrillogenesis, as well as increases the expression and biological activity of CaMKâ…¡, thus suggesting a direct mediating role of CaMKâ…¡in Angâ…¡-induced cardiac remodeling.