Silencing Of Mitogen-activated Protein Kinase 6 Protects Aganist Vascular Remodling In Spontaneously Hypertensive Rat By Targeting NOX4/AKT Signalling Pathway

Objective:Hypertension is a global health problem and is the most important risk factor for the development of cardiovascular disease,and the continuous increase in blood pressure can lead to vascular dysfunction and vascular remodeling.Vascular smooth muscle cells(VSMCs)are located in the middle layer of blood vessels,and when hypertension occurs,VSMCs change from a contractile phenotype to a synthetic phenotype,manifesting a significantly faster rate of proliferation.Mitogen-activated protein kinase 6(MAPK6),a member of atypical mitogen-activated protein kinases,is implicated in regulating vascular cell function.However,the role of MAPK6 in hypertension-induced vascular remodeling remains unclear.This study aims to investigate the function and regulation mechanism of MAPK6 on vascular smooth muscle cells.Methods:Expression of protein and mRNA was detected by RT-PCR and Western Blot;MAPK6 silencing in vascular smooth muscle cells was established.Effects of MAPK6 silencing on proliferation of VSMCs was measured by CCK-8 and Ed U assay.Effects of MAPK6 silencing on migration of VSMCs was detected a wound healing assay;MAPK6 silencing in carotid arteries from SHR was established.Effect of MAPK6 silencing on hypertension induced vascular remodeling was assayed by histological assay;Effcet of ten-eleven translocation 2 knockdown on vascular remodeling and expression of MAPK6 was evaluated using TET2 knockdown mice.Results:Compared with normotensive rats,aortic MAPK6 expression is increased in spontaneously hypertensive rats.MAPK6 silencing reduced VSMCs proliferation by increasing cyclin-dependent kinase inhibitor 1B(p27)expression and decreasing proliferating cell nuclear antigen(PCNA)expression.MAPK6 deletion caused a reduction in VSMC migration which was supported by downregulated expression of matrix metalloprotein 2(MMP2).Silencing MAPK6 also reduced extracellular matrix deposition by downregulating collagen Ia(Col1a)and collagen IIIa(Col3a)expression in VSMCs.Studying the mechanism revealed that MAPK6 silencing attenuated AKT and ERK signaling,which controls VSMC proliferation,and upregulated expression of NADPH oxidase 4(NOX4)and smooth muscle 22(SM22),which is involved with VSMC differentiation.TET2 knockdown increased thickness of tunicae media and enhanced expression of MAPK6 in aorta of TET2 knockdown mice.Conclusion:MAPK6 expression is elevated in hypertension,and silent MAPK6 inhibits the proliferative and migration capacity of VSMC and reduces the expression of Colla and Col3 a,indicating that MAPK6 plays an important role in vascular wall remodeling and hypertension pathogenesis.Figure(nine)table(thirteen)reference(sixty-three)...