Class A1 Scavenger Receptor Inhibits Obesity-related Hypertension

Objectives:Nowadays,obesity is continuously affecting public health and has become the leading cause of death in worldwide.Obesity leads to a series of structural and functional changes in the cardiovascular system,including decreased cardiac output,increased peripheral resistance,and left ventricular hypertrophy.Obesity increases the morbidity and mortality of cardiovascular diseases(CVD).Therefore,in-depth study of obesity-induced CVD pathogenesis,to find more effective prevention and therapy of the target,is of particularly importantance.Class A1 scavenger receptor(SR-A1),a majorpattern recognition receptors(PRRs),participates in regulating multiple biological function in macrophages such as apoptosis,phagocytosis,and cytokines secretion.Our previous study indicated that in obese mice,SR-A1 in adipose tissues could inhibit the secretion of inflammatory cytokines via activating STAT6 signaling and thus exert beneficial effect on insulin resistance.This study is designed to investigate the function and mechanism of SR-A1 in obesity-related hypertensionMethods:RT-PCR,ELISA and flow cytometric analysis were used to examine the expression of SR-A1 in adipose tissues and in bloods.Spontaneous obese mice(ob/ob mice)and diet-induced obese mice were used as the obese mouse models.The mouse blood pressure was measured by implanting radioelemetry pressure transducers into carotid artery.The acetylcholine(Ach)-mediated endothelium-dependent relaxation(EDR)response were observed in isolated aortae.We also examined the expression of macrophage-specific markers and inflammatory genes in perivascular adipose tissue(PVAT)and in blood by RT-PCR and ELISA.RT-PCR,western blot and flow cytometric analysis were applicaed to examine the levels of VEGF-B in adipose tissue and blood.A down-regulation of VEGF-B in mice were achieved by peritoneal injection of lentivirus into mice.Results:We found that the expressional level of SR-A1 in single macrophage was decreased both in obese mice and in obese human beings.Deficiency of SR-A1 increased dramatically blood pressure in spontaneous obese mice as well as in diet-induced obese mice.In addition,Ach-mediated endothelium-dependent relaxation(EDR)response in isolated aortae was significantly impaired in the SR-A1 deficient obese mice.Furthermore,strong macrophage infiltration and inflammatory cytokines(TNF?,IL-1?,IL-6)production were found in the PVAT and plasma of SR-A1 deficient obese mice by measurements of RT-PCR and ELISA.We also found that level of VEGF-B was increased in the PVAT of SR-A1 deficient obese mice.VEGF-B could impair endothelial cell function by transporting more fatty acid.The elvated blood pressure and undermined EDR could be ameliorated by a down-regulation of VEGF-B in vivo.In vitro,we confirmed that SR-A1 could inhibit the expression of VEGF-B in macrophage by activating STAT-6 signaling.Furthermore,SR-A1 could also suppress the secretion of TGF-? in macrophage by activating STAT-3 signaling,which caused a lower epreseeion of VEGF-B in adipocyte.It was shown that vigorous inflammation promoted the expression of VEGF-B and TGF-? in macrophages in the presence of lipids.Conclusions:Conclusively,levels of lipids and inflammatory cytokines were increased in PVAT of obese persons.Elevated lipids and inflammatory cytokines could stimulate macrophages and adipocyte to express more VEGF-B,which caused endothelial dysfunction and hypertension.SR-A1 in macrophages could inhibit the secretion of inflammatory cytokine and suppress the expression of VEGF-B in macrophages and adipocyte by activating STAT6 and STAT3 signaling.Thus,SR-A1 may exert a beneficial effect on obesity-related hypertension.