The Protective Role Of Aldehyde Dehydrogenase2(ALDH2) On Diabetic Cardiomyopathy And Related Mechanism Research

Objective: To investigate the role of mitochondrial aldehyde dehydrogenase2(ALDH2) in different stages of rat diabetic cardiomyopathy (DM) and study whetherthe cardioprotective role of ALDH2was related with improving the expression ofmitofusin2(Mfn2), inhibiting apoptosis happening, and decreasing oxidant stressinjury and cardiac fibrosis. Methods: Diabetic model in male SD rat was induced bysingle intraperitoneal injection of streptozoticin (STZ) at55mg/kg. Hearts isolatedfrom DM4w,8w,12w rats were perfused on a langendorff apparatus. And the rat inDM8w group was drinked with2.5%alcohol at second week, then5â„…alcohol at thirdweek until to eighth week. The ventricular hemodynamic parameters, SOD activity,MDA and hydroxyproline (Hp) contents were measured. The myocardium structurewas observed by light and electron microscopes. The expressions of ALDH2andMfn2at mRNA level of left anterior myocardium were detected by RT-PCR andReal-Time PCR analysis. The protein expressions of myocardial ALDH2and Mfn2were detected by Western blot and IHC. The activities of Caspase-3, Caspase-9weremeasured by spectrophotometry. Results:1. Ventricular hemodynamic parameters:In contrast to control group, there had no particular changes of left ventriculardeveloped pressure (LVDP) and maximal rise/fall rate of left ventricular pressure (±dp/dtmax) in DM4w group; In DM8w and DM12w groups, there had significantdecreases of LVDP and±dp/dtmax. In contrast to DM8w group, LVDP and±dp/dtmax were increased in EtOH+DM8w group.2. Antioxidant ability: In contrastto control group, SOD activity was decreased and MDA content was increased inDM4w, DM8w and DM12w groups. With the development of diabetes, SOD activitywas further decreased and MDA content was further increased. In contrast to DM8wgroup, SOD activity was increased and MDA content was decreased in EtOH+DM8w group.3. The aggravation of cardiac fibrosis: In contrast to control group, Hpcontent was increased in DM4w, DM8w and DM12w groups. With the developmentof diabetes, Hp content was further decreased. In contrast to DM8w group, Hp contentwas decreased in EtOH+DM8w group.4. Light and electron microscopes results:In contrast to control group, there was no particular change of myocardial structure inDM4w group; in DM8w group, cardiac myofibrils arranged irregularly, theintercellular space was dilated, mitochondrial matrix and crista were partly swelling.In DM12w group, cardiac myofibrils were fracture, dissolution, degenerations,mitochondria swelling was serious and cristaes were disappeared. In contrast toDM8w group, the myocardial structure in EtOH+DM8w group was improved.5.RT-PCRå'ŒReal-Time PCR：In contrast to control group, the expressions ofALDH2and Mfn2mRNA levels were reduced in DM4w, DM8w and DM12w groups.With the development of diabetes, ALDH2and Mfn2mRNA were further decreased.In contrast to DM8w group, the expressions of ALDH2and Mfn2mRNA wereincreased in EtOH+DM8w group.6. Protein expressions: IHC: In contrast to controlgroup, the protein expression of Mfn2was reduced in DM4w, DM8w and DM12wgroups. In contrast to DM8w group, the protein expression of Mfn2was increased inEtOH+DM8w group. Western blot: In contrast to control group, the proteinexpressions of ALDH2was resuced in DM8w group. In contrast to DM8w group, theprotein expression of ALDH2was increased in EtOH+DM8w group.7.Apoptosis: Incontrast to DM8w group, the activities of Caspase-3and Caspase-9were decreased inEtOH+DM8w group. Conclusions: The expression of heart mitochondrial ALDH2was low in Diabetic rat. With the development of diabetes, ALDH2expression wasfurther decreased, which may be related to the increase of antioxidant ability, theaggravation of cardiac fibrosis and apoptosis. Activation of ALDH2in diabete rat canplay protective role, increasing Mfn2expression, decreasing oxidant stress injury,cardiac fibrosis and apoptosis may be involved in the protective mechanisms.