Mitochondrial aldehyde dehydrogenase (ALDH2) protects against streptozotocin-induced diabetic cardiomyopathy: role of GSK3β and mitochondrial function.

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: Yingmei Zhang, Sara A Babcock, Nan Hu, Jacalyn R Maris, Haichang Wang, Jun Ren
• Journal: BMC medicine (BMC Med) Vol. 10 Pg. 40 (04 23 2012) ISSN: 1741-7015 [Electronic] England
• PMID: 22524197 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Retracted Publication)

Chemical References

• Forkhead Box Protein O3
• Forkhead Transcription Factors
• FoxO3 protein, mouse
• Ion Channels
• Mitochondrial Proteins
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Ppargc1a protein, mouse
• Sodium-Calcium Exchanger
• Trans-Activators
• Transcription Factors
• Ucp2 protein, mouse
• Uncoupling Protein 2
• ALDH2 protein, mouse
• Aldehyde Dehydrogenase
• Aldehyde Dehydrogenase, Mitochondrial
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Glycogen Synthase Kinase 3
• PTEN Phosphohydrolase
• Sarcoplasmic Reticulum Calcium-Transporting ATPases
• Glucose
• Calcium

Topics

• Aldehyde Dehydrogenase (metabolism)
• Aldehyde Dehydrogenase, Mitochondrial
• Animals
• Apoptosis (drug effects)
• Calcium (metabolism)
• Diabetes Mellitus, Experimental (diagnostic imaging, enzymology, physiopathology, prevention & control)
• Diabetic Cardiomyopathies (diagnostic imaging, enzymology, physiopathology, prevention & control)
• Forkhead Box Protein O3
• Forkhead Transcription Factors (metabolism)
• Glucose (pharmacology)
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Intracellular Space (drug effects, metabolism)
• Ion Channels (metabolism)
• Mice
• Mice, Transgenic
• Mitochondria (drug effects, enzymology)
• Mitochondrial Proteins (metabolism)
• Myocardial Contraction (drug effects)
• Myocytes, Cardiac (drug effects, enzymology, pathology)
• Oxygen Consumption (drug effects)
• PTEN Phosphohydrolase (metabolism)
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Proto-Oncogene Proteins c-akt (metabolism)
• Sarcoplasmic Reticulum Calcium-Transporting ATPases (metabolism)
• Sodium-Calcium Exchanger (metabolism)
• TOR Serine-Threonine Kinases (metabolism)
• Trans-Activators (metabolism)
• Transcription Factors
• Ultrasonography
• Uncoupling Protein 2