CaMKII inhibition in vascular smooth muscle improves angiotensin II–hypertension

Abstract

The multifunctional calcium/calmodulin‐dependent kinase II (CaMKII) is expressed in vascular smooth muscle cells (VSMC) and activated by Angiotensin‐II (Ang‐II). To test the hypothesis that CaMKII in VSMC mediates Ang‐II‐hypertension, we developed transgenic mice that express the specific CaMKII peptide inhibitor CaMKIIN selectively in VSMC (Tg SM CaMKIIN). These mice have a 65 % reduced CaMKII activity in arteries (p<0.01) and identical baseline blood pressure compared to littermate controls. Following Ang‐II infusion at pressor dose, the increase in mean pressure was significantly attenuated (129±4 mmHg vs, 116±3 mmHg, p<0.05). Ang‐II increases Ca2+ influx through L‐type Ca2+ channels (LTCC). Cytosolic Ca2+ ([Ca2+]) rise leads to an increased vascular tone. Compared with littermates, freshly isolated mesenteric VSMC of Ang‐II treated Tg SM CaMKIIN mice had significantly reduced voltage gated L‐type Ca2+ current (ICa), ICa facilitation. Moreover, the [Ca2+] elevation in response to Ang‐II stimulation was reduced by 50 % in VSMC of TgSM CaMKIIN mice (0.045±0.002 vs, 0.025±0.003; ratio340/380; p<0.05) whereas, level of total releasable SR calcium was decreased by 35 %. In conclusion, inhibition of CaMKII in VSMC significantly attenuates Ang‐II induced hypertension through regulation of LTCC and by restoring the calcium homeostasis. CaMKII may be a novel target in treating hypertension.