Mechanisms Of Akap150 In Aerobic Exercise-induced Improvement Of Cerebral Arterial Function In Essential Hypertension

Abstract

A-kinase anchoring protein AKAP150, facilitating transduction events by binding protein kinase Cα (PKCα) to specific cellular microdomains, plays a central role in voltage-gated L-type Ca2+ channel (LTCC) remodeling in vascular smooth muscle during hypertension. Emerging evidence have demonstrated the beneficial effects of regular exercise on reducing blood pressure and improving arterial function in hypertension, however, less is known regarding the cellular mechanisms underlying the vascular changes with exercise. PURPOSE: To investigate the mechanism of AKAP150/PKCα signaling pathway in exercise-mediated LTCC function of cerebral arteries during hypertension. METHODS: 12-week-old male spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were randomly assigned to sedentary (WKY-SED, SHR-SED) and exercise training (WKY-EX, SHR-EX) groups. Exercise groups were performed a moderate-intensity treadmill running (about 55-65% VO2max, 20 m/min, 0 grade, 60 min, 5 days/week). After 12 weeks, artery contraction myography, patch-clamp electrophysiology, Ca2+ image, Western blot and immunofluorescence were used to detect cerebral vascular tone, LTCC whole-cell and single channel currents, Ca2+ sparklets, and AKAP150/PKCα signaling pathway. RESULTS: Exercise attenuated LTCC contribution to cerebral vascular tone regulation (39.0±1.3 vs. 27.5±2.0 %Kmax) and LTCC currents in cerebral arterial myocytes of SHR (−13.2±1.7 vs. −9.6±1.5 pA/pF, both P<0.05). The LTCC channel open probability (nPo) and persistent Ca2+ sparklet activity (nPs) of cerebral arterial myocytes were significantly reduced in SHR-EX as compared with SHR-SED (nPo: 0.08±0.01 vs. 0.12±0.01; nPs: 0.65±0.15 vs. 0.82±0.10; both P<0.05). The protein expression of AKAP150 in cerebral artery was significantly up-regulated in SHR-SED (4.9±0.6), while down-regulated in SHR-EX (1.4±0.2, P<0.05). The colocalization rate of AKAP150 and PKCα at the sarcolemma were lower in cerebral arterial myocytes from SHR-EX than those from SHR-SED (20.1±1.1 vs. 30.0±1.6%, P<0.05). CONCLUSIONS: Chronic exercise inhibits LTCC channel activity and persistent Ca2+ sparklets in vascular smooth muscle via suppression of AKAP150/PKCα signaling pathway, and ameliorates the dysfunction of cerebral arteries during hypertension.