Mitochondrial aldehyde dehydrogenase (ALDH2) protects against streptozotocin-induced diabetic cardiomyopathy: role of GSK3β and mitochondrial function
<p>Abstract</p> <p>Background</p> <p>Mitochondrial aldehyde dehydrogenase (ALDH2) displays some promise in the protection against cardiovascular diseases although its role in diabetes has not been elucidated.</p> <p>Methods</p> <p>This study was...
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| Format: | Article |
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BMC
2012-04-01
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| Series: | BMC Medicine |
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| Online Access: | http://www.biomedcentral.com/1741-7015/10/40 |
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| author | Zhang Yingmei Babcock Sara A Hu Nan Maris Jacalyn R Wang Haichang Ren Jun |
| author_facet | Zhang Yingmei Babcock Sara A Hu Nan Maris Jacalyn R Wang Haichang Ren Jun |
| author_sort | Zhang Yingmei |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Mitochondrial aldehyde dehydrogenase (ALDH2) displays some promise in the protection against cardiovascular diseases although its role in diabetes has not been elucidated.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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 Ca<sup>2+ </sup>defects, including depressed peak shortening and maximal velocity of shortening and relengthening; prolonged duration of shortening and relengthening; and dampened intracellular Ca<sup>2+ </sup>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 Ca<sup>2+ </sup>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. <it>In vitro </it>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.</p> <p>Conclusions</p> <p>In summary, our data revealed that ALDH2 acted against diabetes-induced cardiac contractile and intracellular Ca<sup>2+ </sup>dysregulation, possibly through regulation of apoptosis, glycogen synthase kinase-3β activation and mitochondrial function independent of the global metabolic profile.</p> |
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| institution | Directory Open Access Journal |
| issn | 1741-7015 |
| language | English |
| last_indexed | 2024-12-12T10:19:30Z |
| publishDate | 2012-04-01 |
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| spelling | doaj.art-f3f308dbe4064d88ac507f0813d5033e2022-12-22T00:27:35ZengBMCBMC Medicine1741-70152012-04-011014010.1186/1741-7015-10-40Mitochondrial aldehyde dehydrogenase (ALDH2) protects against streptozotocin-induced diabetic cardiomyopathy: role of GSK3β and mitochondrial functionZhang YingmeiBabcock Sara AHu NanMaris Jacalyn RWang HaichangRen Jun<p>Abstract</p> <p>Background</p> <p>Mitochondrial aldehyde dehydrogenase (ALDH2) displays some promise in the protection against cardiovascular diseases although its role in diabetes has not been elucidated.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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 Ca<sup>2+ </sup>defects, including depressed peak shortening and maximal velocity of shortening and relengthening; prolonged duration of shortening and relengthening; and dampened intracellular Ca<sup>2+ </sup>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 Ca<sup>2+ </sup>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. <it>In vitro </it>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.</p> <p>Conclusions</p> <p>In summary, our data revealed that ALDH2 acted against diabetes-induced cardiac contractile and intracellular Ca<sup>2+ </sup>dysregulation, possibly through regulation of apoptosis, glycogen synthase kinase-3β activation and mitochondrial function independent of the global metabolic profile.</p>http://www.biomedcentral.com/1741-7015/10/40ALDH2cardiac contractiondiabetesGSK3βmitochondrial function |
| spellingShingle | Zhang Yingmei Babcock Sara A Hu Nan Maris Jacalyn R Wang Haichang Ren Jun Mitochondrial aldehyde dehydrogenase (ALDH2) protects against streptozotocin-induced diabetic cardiomyopathy: role of GSK3β and mitochondrial function BMC Medicine ALDH2 cardiac contraction diabetes GSK3β mitochondrial function |
| title | Mitochondrial aldehyde dehydrogenase (ALDH2) protects against streptozotocin-induced diabetic cardiomyopathy: role of GSK3β and mitochondrial function |
| title_full | Mitochondrial aldehyde dehydrogenase (ALDH2) protects against streptozotocin-induced diabetic cardiomyopathy: role of GSK3β and mitochondrial function |
| title_fullStr | Mitochondrial aldehyde dehydrogenase (ALDH2) protects against streptozotocin-induced diabetic cardiomyopathy: role of GSK3β and mitochondrial function |
| title_full_unstemmed | Mitochondrial aldehyde dehydrogenase (ALDH2) protects against streptozotocin-induced diabetic cardiomyopathy: role of GSK3β and mitochondrial function |
| title_short | Mitochondrial aldehyde dehydrogenase (ALDH2) protects against streptozotocin-induced diabetic cardiomyopathy: role of GSK3β and mitochondrial function |
| title_sort | mitochondrial aldehyde dehydrogenase aldh2 protects against streptozotocin induced diabetic cardiomyopathy role of gsk3β and mitochondrial function |
| topic | ALDH2 cardiac contraction diabetes GSK3β mitochondrial function |
| url | http://www.biomedcentral.com/1741-7015/10/40 |
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