Regulator Of G P Rotein Signalling 5 Protects Against Atherosclerosis In Apolipoprotein E-deficient Mice

Atherosclerosis is a crucial pathophysiological condition underlying cardiovascular disease,the leading cause of mortality and morbidity in Western countries.O ver the last dozen years,compelling evidence has demonstrated that atherosclerosis is a chronic inflammatory disease that is initiated by oxidative modification of low-density lipoprotein-induced activation of endothelial dysfunction and that the subsequent secretion of chemokines and adhesion molecules attract monocytes,which adhere to and migrate into the atherosclerotic lesions,where they differentiate into macrophages.Recently,the recognition of the atherosclerosis process,including the deter ?? ant features of “vulnerable plaques”,has been receiving substantial attention as a risk factor for the occurrence of various acute coronary heart disease(CHD)events: myocardial infarction,sudden cardiac death,and stroke.Thus,identifying the underlying molecular mechanisms that may attenuate atherosclerotic plaque progression and ultimate rupture is necessary for developing effective preventive and therapeutic strategies.Regulator of G protein signalling(RGS)proteins is the collective name for a family of proteins that has been identified as negative regulators of G protein-mediated receptor signalling pathways,which are required for multiple biological processes through the control of cellular function;these proteins act as GAPs(GTPase-activating proteins)and stimulate the hydrolysis of the G?-bound GTP back to GDP,resulting in the reassociation of the G?? subunit.As a member of the B/R4 family,RGS5 expression is enriched in the aorta,heart,and skeletal muscle,particularly in pericytes,smooth muscle cells,and endothelial cells of cardiovascular tissues.To date,an increasing number of studies support the important role of RGS5 in endothelial function.RGS5 has been identified as the first marker of angiogenic pericytes and is responsible for vessel remodelling correlated with skin wound healing and tumour angiogenesis.RGS5 deficiency results in pericyte maturation and vascular normalisation and consequently improves the status of tumour hypoxia and reduces the leakiness of angiogenic vessels;this effect is similar to the observation that after transient cerebral ischaemia,the loss of RGS5,especially in pericytes surrounding brain capillaries,ameliorates oedema by reducing vascular permeability.Moreover,RGS5 deletion increases dyslipidaemia,obesity,adipose tissue deposition,hepatic steatosis,and circulating inflamma tion.However,little information is available on the function of RGS5 during the development of atherosclerosis.To explored the effect of RGS5 on atherosclerosis and the potential mechanism.First,we observed decreased expression of RGS5 in the atheroma tous plaque from humans and Apo E-deficient male mice.Then RGS5-/-Apo E-/-and Apo E-/-littermates were used in our study and fed with high-fat diet for 28 weeks.Through analysing the morphology of atherosclerotic lesions in aortic root and total aorta surface,RGS5-/-Apo E-/-mice significantly accelerate the progression of atherosclerosis.Using quantitative real-time PC R,the m RNA levels of pro-inflammatory markers,IL-6,IL-1b,and TNF-a were increased in the atherosclerotic lesions of RGS5-/-Apo E-/-mice,whereas the anti-inflammatory IL-10 showed the opposite result.By immunofluorescence staining,RGS5 deficiency increased the number of apoptotic endothelial cells and macrophages,as well as the expression of adhesion molecule VCAM-1,ICAM-1.Mechanistically,we noticed RGS5 ablation can activate the NF-k B and MEK-ERK1/2 signalling pathway.In conclusion,we found that RGS5 ablation associating with endothelial cells accelerates atherogenesis and plaque instability by contributing to endothelial dysfunction and enhanced vascular inflammation through the activation of the NF-k B and MEK-ERK1/2 signalling pathways.Further clinical investigation is needed to determine whether increased RGS5 levels constitute an effective treatment for underlying atherosclerosis in patients with CHD or whether RGS5 is a potential target for the prevention of atherogenesis and the stabilisation of atherosclerotic plaques.