The effects of amrinone on cardiac contraction and relaxation were assessed in isolated, perfused rat hearts. It was found that the left ventricular developed pressure (LVDP), dp/dtmax and -da/dtmax did not significan...The effects of amrinone on cardiac contraction and relaxation were assessed in isolated, perfused rat hearts. It was found that the left ventricular developed pressure (LVDP), dp/dtmax and -da/dtmax did not significantly increase . and the time constant (τ) did not markedly shorten with perfusion of low concentration ( 1 nmol/L , 100 nmol/L) of amrinone. The perfusion with higher concentration (1000 nmol/L) of amrinone reduced LVDP (P<0. 01 ) ,dp/dtmax (P<0.01) , -dp/dtmax (P<0. 01). and prolonged τ(P< 0. 05) significaiatly. It was assumed that amrinone has no direct positive inotropic effect. and can not improve cardiac relaxation. On the contrary, the cardiac contraction and relax ation will be inhibited at higher concentration of amrinone.展开更多
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 cardiomy...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.展开更多
文摘The effects of amrinone on cardiac contraction and relaxation were assessed in isolated, perfused rat hearts. It was found that the left ventricular developed pressure (LVDP), dp/dtmax and -da/dtmax did not significantly increase . and the time constant (τ) did not markedly shorten with perfusion of low concentration ( 1 nmol/L , 100 nmol/L) of amrinone. The perfusion with higher concentration (1000 nmol/L) of amrinone reduced LVDP (P<0. 01 ) ,dp/dtmax (P<0.01) , -dp/dtmax (P<0. 01). and prolonged τ(P< 0. 05) significaiatly. It was assumed that amrinone has no direct positive inotropic effect. and can not improve cardiac relaxation. On the contrary, the cardiac contraction and relax ation will be inhibited at higher concentration of amrinone.
基金supported in part by the State Key Laboratory of Dampness Syndrome of Traditional Chinese Medicine jointly established by Guangdong Province and the Ministry(SZ2022KF10)Scientific Research Initiation Project of Guangdong Provincial Hospital of Traditional Chinese Medicine(2021KT1709)+1 种基金Guangzhou School(College)Joint Sponsorship Project for Fundamental and Applied Research(202201020605)Program of Shanghai Academic/Technology Research Leader(20XD1420900).
文摘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.
