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Mitochondrial aldehyde dehydrogenase (ALDH2) protects against streptozotocin-induced diabetic cardiomyopathy: role of GSK3β and mitochondrial function.
BMC Med. 2012 Apr 23; 10:40.BM

Abstract

BACKGROUND

Mitochondrial aldehyde dehydrogenase (ALDH2) displays some promise in the protection against cardiovascular diseases although its role in diabetes has not been elucidated.

METHODS

This study was designed to evaluate the impact of ALDH2 on streptozotocin-induced diabetic cardiomyopathy. Friendly virus B(FVB) and ALDH2 transgenic mice were treated with streptozotocin (intraperitoneal injection of 200 mg/kg) to induce diabetes.

RESULTS

Echocardiographic evaluation revealed reduced fractional shortening, increased end-systolic and -diastolic diameter, and decreased wall thickness in streptozotocin-treated FVB mice. Streptozotocin led to a reduced respiratory exchange ratio; myocardial apoptosis and mitochondrial damage; cardiomyocyte contractile and intracellular Ca2+ defects, including depressed peak shortening and maximal velocity of shortening and relengthening; prolonged duration of shortening and relengthening; and dampened intracellular Ca2+ rise and clearance. Western blot analysis revealed disrupted phosphorylation of Akt, glycogen synthase kinase-3β and Foxo3a (but not mammalian target of rapamycin), elevated PTEN phosphorylation and downregulated expression of mitochondrial proteins, peroxisome proliferator-activated receptor γ coactivator 1α and UCP-2. Intriguingly, ALDH2 attenuated or ablated streptozotocin-induced echocardiographic, mitochondrial, apoptotic and myocardial contractile and intracellular Ca2+ anomalies as well as changes in the phosphorylation of Akt, glycogen synthase kinase-3β, Foxo3a and phosphatase and tensin homologue on chromosome ten, despite persistent hyperglycemia and a low respiratory exchange ratio. In vitro data revealed that the ALDH2 activator Alda-1 and glycogen synthase kinase-3β inhibition protected against high glucose-induced mitochondrial and mechanical anomalies, the effect of which was cancelled by mitochondrial uncoupling.

CONCLUSIONS

In summary, our data revealed that ALDH2 acted against diabetes-induced cardiac contractile and intracellular Ca2+ dysregulation, possibly through regulation of apoptosis, glycogen synthase kinase-3β activation and mitochondrial function independent of the global metabolic profile.

Authors+Show Affiliations

Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

22524197

Citation

Zhang, Yingmei, et al. "Mitochondrial Aldehyde Dehydrogenase (ALDH2) Protects Against Streptozotocin-induced Diabetic Cardiomyopathy: Role of GSK3β and Mitochondrial Function." BMC Medicine, vol. 10, 2012, p. 40.
Zhang Y, Babcock SA, Hu N, et al. Mitochondrial aldehyde dehydrogenase (ALDH2) protects against streptozotocin-induced diabetic cardiomyopathy: role of GSK3β and mitochondrial function. BMC Med. 2012;10:40.
Zhang, Y., Babcock, S. A., Hu, N., Maris, J. R., Wang, H., & Ren, J. (2012). Mitochondrial aldehyde dehydrogenase (ALDH2) protects against streptozotocin-induced diabetic cardiomyopathy: role of GSK3β and mitochondrial function. BMC Medicine, 10, 40. https://doi.org/10.1186/1741-7015-10-40
Zhang Y, et al. Mitochondrial Aldehyde Dehydrogenase (ALDH2) Protects Against Streptozotocin-induced Diabetic Cardiomyopathy: Role of GSK3β and Mitochondrial Function. BMC Med. 2012 Apr 23;10:40. PubMed PMID: 22524197.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mitochondrial aldehyde dehydrogenase (ALDH2) protects against streptozotocin-induced diabetic cardiomyopathy: role of GSK3β and mitochondrial function. AU - Zhang,Yingmei, AU - Babcock,Sara A, AU - Hu,Nan, AU - Maris,Jacalyn R, AU - Wang,Haichang, AU - Ren,Jun, Y1 - 2012/04/23/ PY - 2012/01/18/received PY - 2012/04/23/accepted PY - 2012/4/25/entrez PY - 2012/4/25/pubmed PY - 2012/7/7/medline SP - 40 EP - 40 JF - BMC medicine JO - BMC Med VL - 10 N2 - BACKGROUND: Mitochondrial aldehyde dehydrogenase (ALDH2) displays some promise in the protection against cardiovascular diseases although its role in diabetes has not been elucidated. METHODS: This study was designed to evaluate the impact of ALDH2 on streptozotocin-induced diabetic cardiomyopathy. Friendly virus B(FVB) and ALDH2 transgenic mice were treated with streptozotocin (intraperitoneal injection of 200 mg/kg) to induce diabetes. RESULTS: Echocardiographic evaluation revealed reduced fractional shortening, increased end-systolic and -diastolic diameter, and decreased wall thickness in streptozotocin-treated FVB mice. Streptozotocin led to a reduced respiratory exchange ratio; myocardial apoptosis and mitochondrial damage; cardiomyocyte contractile and intracellular Ca2+ defects, including depressed peak shortening and maximal velocity of shortening and relengthening; prolonged duration of shortening and relengthening; and dampened intracellular Ca2+ rise and clearance. Western blot analysis revealed disrupted phosphorylation of Akt, glycogen synthase kinase-3β and Foxo3a (but not mammalian target of rapamycin), elevated PTEN phosphorylation and downregulated expression of mitochondrial proteins, peroxisome proliferator-activated receptor γ coactivator 1α and UCP-2. Intriguingly, ALDH2 attenuated or ablated streptozotocin-induced echocardiographic, mitochondrial, apoptotic and myocardial contractile and intracellular Ca2+ anomalies as well as changes in the phosphorylation of Akt, glycogen synthase kinase-3β, Foxo3a and phosphatase and tensin homologue on chromosome ten, despite persistent hyperglycemia and a low respiratory exchange ratio. In vitro data revealed that the ALDH2 activator Alda-1 and glycogen synthase kinase-3β inhibition protected against high glucose-induced mitochondrial and mechanical anomalies, the effect of which was cancelled by mitochondrial uncoupling. CONCLUSIONS: In summary, our data revealed that ALDH2 acted against diabetes-induced cardiac contractile and intracellular Ca2+ dysregulation, possibly through regulation of apoptosis, glycogen synthase kinase-3β activation and mitochondrial function independent of the global metabolic profile. SN - 1741-7015 UR - https://www.unboundmedicine.com/medline/citation/22524197/Mitochondrial_aldehyde_dehydrogenase__ALDH2__protects_against_streptozotocin_induced_diabetic_cardiomyopathy:_role_of_GSK3β_and_mitochondrial_function_ L2 - https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-10-40 DB - PRIME DP - Unbound Medicine ER -