Abstract 879: Aldehyde Dehydrogenase Activator 1 (Alda-1) Attenuates Coronary Endothelial Dysfunction-Mediated Cardiac Damage in ALDH2*2 Diabetic Mice

Aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme in heart, can remove 4-hydroxy-2-nonenal (4-HNE), a toxic by-products of oxidative stress induced by diabetes and ischemia-reperfusion (I/R) injury. A common inactivating mutation of ALDH2 (termed ALDH2*2) was found in 8% of the world’s population, which causes lower ALDH2 activity in mutation carriers. We hypothesized that Alda-1, the only known activator of both ALDH2 and ALDH2*2 mutation, is able to protect heart from I/R injury in diabetic mice with/without ALDH2*2 mutation. Adult male ALDH2*2 mutant and C57B6 wild-type (WT) mice at 3-4 months of age were made hyperglycemic with streptozotocin injection (150 mg/kg. i.p.). Three weeks after injection, Alzet osmotic pumps were implanted subcutaneously to deliver Alda-1 (10 mg/kg) or vehicle. Mice were sacrificed after one day of pump implantation. Hearts were isolated and subjected to 30-minute ischemic followed by 90-minute reperfusion in a Langendorff apparatus. The basal myocardial ALDH2 activity in diabetic ALDH2*2 mutant was significantly lower than in diabetic WT mice (0.50±0.23 vs 0.83±0.08 mmol/min/μg, -39.8%, p<0.05). Alda-1 significantly increased myocardial ALDH2 activity in both ALDH2*2 (1.17±0.38 mmol/min/μg, +134.0%, p<0.05) and WT (1.46±0.40 mmol/min/μg, +75.9%, p<0.05) diabetic mice. Compared with vehicle, Alda-1 significantly improved left ventricular pressure (LVP), and decreased infarcted areas (IA) both in ALDH2*2 (LVP: 4.30±2.03 vs 15.77±8.99 mmHg, +266.7%, p<0.05; IA: 75.17%±9.49 vs 40.46%±7.20, -46.2%, p<0.05) and WT (LVP: 14.22±7.92 vs 21.96±4.32 mmHg, +54.4%, p<0.05; IA: 42.44%±8.60 vs 28.61%±8.55, -32.6%, p<0.05) subjected to I/R injury. Western-blots showed that Alda-1 decreased levels of 4-HNE protein adducts, and increased levels of mitochondrial complex V in both ALDH2*2 and WT mice. Our data suggest that one-day Alda-1 treatment can confer cardio-protective effects against I/R injury in ALDH2*2 diabetic mice possibly accelerating the detoxification of toxic 4-HNE and thereby protecting mitochondria.

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Decreased Aldehyde Dehydrogenase (ALDH)2 Activity Contributes to Coronary Endothelial Dysfunction in Diabetic Cardiomyopathy

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2017.07.019 ◽

2017 ◽

Vol 112 ◽

pp. 135-136 ◽

Cited By ~ 1

Author(s):

Guodong Pan ◽

Mandar Deshpande ◽

Suresh S. Palaniyandi

Keyword(s):

Endothelial Dysfunction ◽

Aldehyde Dehydrogenase ◽

Diabetic Cardiomyopathy ◽

Coronary Endothelial Dysfunction

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Diabetic Aldehyde Dehydrogenase 2 Mutant (ALDH2*2) Mice Are More Susceptible to Cardiac Ischemic‐Reperfusion Injury Due to 4‐Hydroxy‐2‐Nonenal Induced Coronary Endothelial Cell Damage

Journal of the American Heart Association ◽

10.1161/jaha.121.021140 ◽

2021 ◽

Author(s):

Guodong Pan ◽

Bipradas Roy ◽

Suresh Selvaraj Palaniyandi

Keyword(s):

Endothelial Cell ◽

Reperfusion Injury ◽

Aldehyde Dehydrogenase ◽

Cardiac Dysfunction ◽

Ex Vivo ◽

Coronary Perfusion ◽

Myocardial Infarct Size ◽

Diabetic Mice ◽

Aldehyde Dehydrogenase 2 ◽

Cardiac Damage

Background Aldehyde dehydrogenase‐2 (ALDH2), a mitochondrial enzyme, detoxifies reactive aldehydes such as 4‐hydroxy‐2‐nonenal (4HNE). A highly prevalent E487K mutation in ALDH2 (ALDH2*2) in East Asian people with intrinsic low ALDH2 activity is implicated in diabetic complications. 4HNE‐induced cardiomyocyte dysfunction was studied in diabetic cardiac damage; however, coronary endothelial cell (CEC) injury in myocardial ischemia‐reperfusion injury (IRI) in diabetic mice has not been studied. Therefore, we hypothesize that the lack of ALDH2 activity exacerbates 4HNE‐induced CEC dysfunction which leads to cardiac damage in ALDH2*2 mutant diabetic mice subjected to myocardial IRI. Methods and Results Three weeks after diabetes mellitus (DM) induction, hearts were subjected to IRI either in vivo via left anterior descending artery occlusion and release or ex vivo IRI by using the Langendorff system. The cardiac performance was assessed by conscious echocardiography in mice or by inserting a balloon catheter in the left ventricle in the ex vivo model. Just 3 weeks of DM led to an increase in cardiac 4HNE protein adducts and, cardiac dysfunction, and a decrease in the number of CECs along with reduced myocardial ALDH2 activity in ALDH2*2 mutant diabetic mice compared with their wild‐type counterparts. Systemic pretreatment with Alda‐1 (10 mg/kg per day), an activator of both ALDH2 and ALDH2*2, led to a reduction in myocardial infarct size and dysfunction, and coronary perfusion pressure upon cardiac IRI by increasing CEC population and coronary arteriole opening. Conclusions Low ALDH2 activity exacerbates 4HNE‐mediated CEC injury and thereby cardiac dysfunction in diabetic mouse hearts subjected to IRI, which can be reversed by ALDH2 activation.

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Role of superoxide anion in coronary endothelial dysfunction in type 2 diabetic mice

The FASEB Journal ◽

10.1096/fasebj.26.1_supplement.1129.8 ◽

2012 ◽

Vol 26 (S1) ◽

Author(s):

Young-Eun Cho ◽

Meenal Pangare ◽

Ayako Makino

Keyword(s):

Endothelial Dysfunction ◽

Superoxide Anion ◽

Diabetic Mice ◽

Coronary Endothelial Dysfunction ◽

Type 2 Diabetic

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Exercise Training Prevents Coronary Endothelial Dysfunction in Type 2 Diabetic Mice

American Journal of Biomedical Sciences ◽

10.5099/aj110400241 ◽

2011 ◽

pp. 241-252 ◽

Cited By ~ 27

Author(s):

Sewon Lee ◽

Yoonjung Park ◽

Cuihua Zhang

Keyword(s):

Endothelial Dysfunction ◽

Exercise Training ◽

Diabetic Mice ◽

Coronary Endothelial Dysfunction ◽

Type 2 Diabetic

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Abstract 038: Hyperglycemia Mediated Cardiac Damage in High-Fat Fed E487K Aldehyde Dehydrogenase 2 (ALDH 2*2) Mutant Diabetic Mice: Role for ALDH2 Activation

Hypertension ◽

10.1161/hyp.68.suppl_1.038 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Guodong Pan ◽

Suresh Palaniyandi

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Cardiac Function ◽

Aldehyde Dehydrogenase ◽

Diabetic Mice ◽

High Fat ◽

Aldehyde Dehydrogenase 2 ◽

Cardiac Damage

Aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme in the heart, detoxifies reactive aldehydes and protects heart from oxidative stress. East Asians (~700 million) are carriers of E487K point mutation of ALDH2 (ALDH2*2) with intrinsically low ALDH2 activity. ALDH2*2 is associated with increased maternal inheritance of diabetes mellitus (DM), and DM-induced neuropathy and vasculopathy. However the pathophysiology of diabetic cardiac damage.is not studied in ALDH2*2 carriers. DM is a polygenic disease and DM-induced cardiac damage may be multifactorial. However we hypothesis that hyperglycemia-induced oxidative stress mediated 4-hydroxy-2-nonel (4HNE) toxicity contributes to the cardiac damage in ALDH2*2 mutant mice (low intrinsic ALDH2 activity) with type-2 diabetes. We induced type-2 diabetes by feeding high-fat diet and found they developed hyperglycemia (blood glucose (BG) levels increased to 357 ± 100 mg/dl vs 137 ± 7 mg/dl) and insulin resistance as measured by glucose tolerance test (GTT) (BG levels 408 ± 50 mg/dl vs 165 ± 18 mg/dl at 2 hours after GTT). To delineate the role of hyperglycemia, we treated the diabetic mice with a sodium-glucose co-transporter 2 (SGLT2) inhibitor, Empaglifuzin (EMP) (3mg/kg/day) or Vehicle for 8 weeks. EMP reduced BG levels from 502 ± 75 mg/dl to 193 ± 50 mg/dl by enhancing urinary glucose excretion. Surprisingly EMP reversed insulin resistance as maintained similar BG levels before and after 2 hours of GTT; 190 ± 23 mg/dl vs 188 ± 16 mg/dl. EMP also increased ALDH2 activity to 22 ± 8 % from 7 ± 3 % and 4HNE protein adduct levels. Finally EMP improved cardiac function i.e. % fractional shortening (FS) is increased to 70 ± 4 compared to 53 ± 10. Our data suggested hyperglycemia partially contribute to the diabetic cardiac damage via increasing 4HNE protein adducts. Alda-1 (10 mg/kg/day) treatment further augmented ALDH2 activity, reduced 4HNE adducts and improved cardiac function in EMP-treated ALDH2*2 mice. Thus hyperglycemia mediated secondary events in type-2 DM are significant pathomechanism of the cardiac damage. In conclusion, we propose ALDH2 activation may ameliorate diabetic patients from cardiac complications who receive glucose lowering treatments.

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