The Effect of Aerobic Exercise on the Improvement of the Mesenteric Artery Function in Hypertension through PKCα/Ca_V1.2 Pathway

Objective:To investigate the relationships between PKCα and Ca_V1.2 channel and the role of PKCα/Ca_V1.2 pathway in aerobic exercise-induced improvement of the function of mesenteric artery in hypertension.Methods:12 weeks old,male,spontaneously hypertensive rats(SHR) and Wistar-Kyoto rats(WKY) were randomly divided into sedentary groups(SHR-SED,WKY-SED) and exercise training groups(SHR-EX,WKY-EX),respectively.The exercise training groups were performed a moderate-intensity treadmill running protocol for 12 weeks.After the training intervention,the mesenteric arteries were obtained to detect the vascular contraction characteristics and the role of PKCα/Ca_V1.2 signaling pathway in the regulation of vascular tension by using isometric contraction test.The smooth muscle cells were separated to measure the Ca_V1.2 channel current and the effect of PKCα on Ca_V1.2 channel current.Immunofluorescence was performed to detect the expression of PKCα and its colocalization ratio with Ca_V1.2 channel α1 C subunit.Results:1) Aerobic exercise training was significantly reduced the weight、heart rate and blood pressure of SHR-EX and WKY-EX groups(P<0.05);2) The sensitivity of the Ca_V1.2 channel agonist BayK8644 and the inhibitor Nifedipine was significantly higher in the SHR-SED group than that of the WKY-SED group when hypertension occurs(P<0.05).However,aerobic exercise training could effectively inhibit the increased sensitivity of the SHR to BayK8644 and Nifedipine(P<0.05);3) PKCα inhibitor Gö6976 can induce vasodilation,the sensitivity of Gö6976 was significantly higher in the SHR-SED group than WKY-SED group(P<0.05).Compared with the SHR-SED group,the sensitivity of mesenteric artery to Gö6976 in SHR-EX group was significantly lower(P<0.05).But there was no significant difference between WKY-EX group and WKY-SED group(P>0.05);4) PKC agonist PDBu could induce a concentration-dependent increase in vascular tension,while the systolic response induced by PDBu was decreased after preincubation of Gö6976 inhibited PKCα in each group.In addition,WKY-EX and SHR-EX groups showed no significant difference in the systolic response induced by PDBu compared with their sedentary control groups respectively(P>0.05).The vascular diastolic degree of each group was decreased after the addition of Nifedipine,but there was no significant difference between the exercise training group and the sedentary group(P>0.05);5) Gö6976 reduced the current amplitude of Ca_V1.2 channel in each group.Compared with WKY-SED group,the SHR-SED group showed a great reduction in Ca_V1.2 channel current(P<0.05),while aerobic exercise significantly inhibited the response of Ca_V1.2 channel to Gö6976 in the hypertensive mesenteric artery(P<0.05).However,there was no significant difference in Ca_V1.2 channel current reduction between the WKY-SED group and the WKY-EX group(P>0.05);6) Immunofluorescence results showed that the expression of PKCα and its colocalization ratio with Ca_V1.2 channel α1 C subunit were significantly upregulated in the SHR-SED group,but the upregulation was effectively inhibited by aerobic exercise training(P<0.05).Conclusion:Aerobic exercise training can effectively reduce the body weight and blood pressure of SHR,and inhibit the hypertension-induced upregulation of PKCα expression,which result in the regulation Ca_V1.2 channel function and improve hypertension symptoms.In other words,the aerobic exercise training can inhibit the upregulation of PKCα/Ca_V1.2 signaling pathway on the vascular smooth muscle of mesenteric artery during hypertension and then improve the function of vascular smooth muscle.