Angiotensin Ⅱ promotes NO production, inhibits apoptosis and enhances adhesion potential of bone marrow-derived endothelial progenitor cells

Endothelial progenitor cells （EPCs） participate in the processes of postnatal neovascularization and re-endothelialization in response to tissue ischemia and endothelial injury. The level of EPCs present has been found to be directly associated with the outcome of cardiovascular diseases, and could be regulated by stimulatory or inhibitory factors. Given the close relationship between angiotensin Ⅱ （AngⅡ） and the cardiovascular＇ system, we investigated the effect of AngⅡ on the activities of bone marrow （BM）-derived EPCs. Cells were isolated from BM of rats by density gradient centrifugation. Administration of AngⅡ significantly promoted nitric oxide （NO） release, inhibited EPC apoptosis and enhanced EPC adhesion potential. All of these AngⅡ-mediated effects on EPCs were attenuated by pretreatment with valsartan or L-NAME. Moreover, both LY294002 and wortmannin abolished the anti-apoptotic effect of AngⅡ. Western blot analyses indicated that endothelial NO synthase （eNOS） protein and phosphorylated Akt increased with the treatment of AngⅡ in EPCs. Thus, AngⅡ improved several activities of EPCs through AngⅡ type 1 receptor （AT1R）, which may represent a possible mechanism linking AnglI and ATIR with angiogenesis. Additionally, AngⅡ-induced NO synthesis through eNOS in EPCs regulates apoptosis and adhesion, and the PI3-kinase/Akt pathway has an essential role in AngⅡ-induced antiapoptosis signaling.

Mitochondrial aldehyde dehydrogenase rescues against diabetic cardiomyopathy through GSK3β-mediated preservation of mitochondrial integrity and Parkin-mediated mitophagy

Mitochondrial aldehyde dehydrogenase(ALDH2)offers proven cardiovascular benefit,although its impact on diabetes remains elusive.This study examined the effects of ALDH2 overexpression and knockout on diabetic cardiomyopathy and the mechanism involved with a focus on mitochondrial integrity.Mice challenged with streptozotocin(STZ,200 mg/kg,via intraperitoneal injection)exhibited pathological alterations,including reduced respiratory exchange ratio,dampened fractional shortening and ejection fraction,increased left ventricular end-systolic and diastolic diameters,cardiac remodeling,cardiomyocyte contractile anomalies,intracellular Ca2+defects,myocardial ultrastructural injury,oxidative stress,apoptosis,and mitochondrial damage,which were overtly attenuated or accentuated by ALDH2 overexpression or knockout,respectively.Diabetic patients also exhibited reduced plasma ALDH2 activity,cardiac remodeling,and diastolic dysfunction.In addition,STZ challenge altered expression levels of mitochondrial proteins(PGC-1αand UCP2)and Ca2+regulatory proteins(SERCA,Na+–Ca2+exchanger,and phospholamban),dampened autophagy and mitophagy(LC3B ratio,TOM20,Parkin,FUNDC1,and BNIP3),disrupted phosphorylation of Akt,GSK3β,and Foxo3a,and elevated PTEN phosphorylation,most of which were reversed or worsened by ALDH2 overexpression or knockout,respectively.Furthermore,the novel ALDH2 activator torezolid,as well as the classical ALDH2 activator Alda-1,protected against STZ-or high glucose-induced in vivo or in vitro cardiac anomalies,which was nullified by inhibition of Akt,GSK3β,Parkin,or mitochondrial coupling.Our data discerned a vital role for ALDH2 in diabetic cardiomyopathy possibly through regulation of Akt and GSK3βactivation,Parkin mitophagy,and mitochondrial function.