Study On The Mechanism And Intervention Of Chronic Intermittent Hypoxia Causing Cardiovascular System And Liver Damage

Backgrond: Endoplasmic reticulum(ER)stress is known to play key roles in the development of endothelial cell apoptosis caused by chronic intermittent hypoxia(CIH).However,how CIH causes ER stress is still unclear.And the angiotensin ?–phospholipase C–inositol-1,4,5-triphosphate(Ang?-PLC-IP3)signaling pathway has been demonstrated to induce ER stress.The purpose of this study is to explore whether the Ang?-PLC-IP3 pathway is involved in the vascular damage induced by CIH,whether the Ang?-PLC-IP3 pathway is involved in ER stress induced by CIH and whether losartan,a selective angiotensin ? type 1 receptor(AT1R)blocker,could suppress endothelial cell apoptosis caused by CIH.Methods: We divided 64 eight-week-old SD rats into eight groups of eight each: RA group,RA+losartan group,CIH group,CIH+losartan group,RA+U73122(a selective PLC inhibitor)group,RA+losartan+U73122 group,CIH+U73122 group,and CIH+losartan+U73122 group.The endothelial apoptosis in the aortic arches of rats was detected by terminal deoxynucleotidyl transferase mediated d UTP-biotin nick end labeling(TUNEL).The expression levels of ER stress markers was detected by immunohistochemistry,quantitative real time PCR(RT-q PCR)and western blotting(WB).The expression of inositol triphosphate receptor(IP3R)and AT1 R at the protein level was detected by WB,and the level of Ang ? in the plasma was detected by enzyme-lined immunosorbent assay(ELISA).Results: Losartan prevented increases in PLC-?1 and IP3 R protein levels and inhibited ER stress markers induced by CIH.Addition of U73122 reproduced all the protective effects of losartan.Losartan administration greatly decreased CIH-caused endothelial cell apoptosis.Conclusions: This study showed that the Ang?-PLC-IP3 pathway is involved in ER stress induced by CIH and that pre-losartan administration ameliorates endothelial cell apoptosis following CIH partly via inhibition of the Ang?-PLC-IP3 pathway and ER stress.Background: Atorvastatin is proven to ameliorate cardiac hypertrophy induced by chronic intermittent hypoxia(CIH).However,little is known about the mechanism by which atorvastatin modulates CIH-induced cardiac hypertrophy,and whether specific hypertrophy-related micro RNAs are involved in the modulation.Mi R-31 plays key roles in the development of cardiac hypertrophy induced by ischemia/hypoxia.This study examined whether miR-31 was involved in the protective role of atorvastatin against CIH-induced myocardial hypertrophy.Methods: H9c2 cells were subjected to 8-h intermittent hypoxia per day in the presence or absence of atorvastatin for 5 days.The size of cardiomyocytes was determined by immunofluorescence.Quantitative real time PCR(RT-q PCR)was used to detect the expressions of miR-31,ANP,BNP and MYH7 in cardiomyocytes,and the expression of caspase 3 in cardiomyocytes was detected by western blotting(WB).Mi R-31 mimic or Ro31-8220,a specific inhibitor of protein kinase C epsilon(PKC?),was used to determine the role of miR-31 in the anti-hypertrophic effect of atorvastatin on cardiomyocytes.PKC? in the cardiomyocytes with miR-31 upregulation or downregulation was detected using RT-q PCR and WB.Results: The results showed that CIH induced obvious enlargement of cardiomyocytes,which was paralleled with increased atrial natriuretic peptide(ANP),brain natriuretic peptide(BNP),and slow/beta cardiac myosin heavy-chain(MYH7)m RNA levels.All these changes were reversed by the treatment with atorvastatin.Meanwhile,miR-31 was increased by CIH in vitro.Of note,the atorvastatin pretreatment significantly increased the m RNA and protein expression of PKC?and decreased that of miR-31.Moreover,overexpression of miR-31 abolished the anti-hypertrophic effect of atorvastatin on cardiomyocytes.Upregulation and downregulation of miR-31 respectively decreased and increased the m RNA and protein expression of PKC?.Conclusions: These results suggest that atorvastatin provides the cardioprotective effects against CIH probably via up-regulating PKC? and down-regulating miR-31.Background: Hepatic steatosis that occasionally results in nonalcoholic steatohepatitis(NASH)is related to obstructive sleep apnea(OSA).Many studies have shown that autophagy exerts protective effects on liver damage caused by various diseases and melatonin exhibits hepatoprotective properties.However,the mechanisms of liver injury induced by chronic intermittent hypoxia(CIH)and the effect of melatonin on the regulation of liver injury remain unclear.This study was aimed to evaluate the role of CIH in steatohepatitis progression and the regulatory function of melatonin on fatty liver sensitivity to CIH injury,mainly focusing on autophagy signaling.Methods: A high-fat diet(FD)-induced obesity mouse model was subjected to intermittent hypoxia/normoxia events for approximately 8 h per day using an autophagy agonist,rapamycin,or an inhibitor,3-methyladenine(3-MA),and SRT1720,a sirtuin 1(SIRT1)activator,or sirtinol,a SIRT1 inhibitor,with or without melatonin for a total of six successive weeks,followed by assessment of expression of autophagy-related genes and activity of serum aminotransferase as well as histological evaluation of tissue morphology.Results: Neither FD nor CIH alone causes significant liver injury;however,the combination yielded higher serum aminotransferase activities and more severe histological changes accompanied by a decrease in autophagy activity.Melatonin markedly inhibited FD/CIH-stimulated liver injury by enhancing autophagy.In contrast,SIRT1 inhibition resulted in a decrease in the expression of melatonin-induced autophagy-related genes as well as diminished its protective effects on FD/CIH-induced liver injury.Conclusions: These results suggest that melatonin could ameliorate FD/CIH-induced hepatocellular damage by activating SIRT1-mediated autophagy signaling.