title: Cardiac Mitochondrial Respiratory Dysfunction and Tissue Damage in Chronic Hyperglycemia Correlate with Reduced Aldehyde Dehydrogenase-2 Activity.
abstract: Aldehyde dehydrogenase (ALDH) 2 is a mitochondrial isozyme of the heart involved in the metabolism of toxic aldehydes produced from oxidative stress. We hypothesized that hyperglycemia-mediated decrease in ALDH2 activity may impair mitochondrial respiration and ultimately result in cardiac damage. A single dose (65 mg/kg; i.p.) streptozotocin injection to rats resulted in hyperglycemia with blood glucose levels of 443 ± 9 mg/dl versus 121 ± 7 mg/dl in control animals, p<0.0001, N = 7-11. After 6 months of diabetes mellitus (DM) induction, the rats were sacrificed after recording the functionality of their hearts. Increase in the cardiomyocyte cross sectional area (446 ± 32 μm2 Vs 221 ± 10 μm2; p<0.0001) indicated cardiac hypertrophy in DM rats. Both diastolic and systolic dysfunctions were observed with DM rats compared to controls. Most importantly, myocardial ALDH2 activity and levels were reduced, and immunostaining for 4HNE protein adducts was increased in DM hearts compared to controls. The mitochondrial oxygen consumption rate (OCR), an index of mitochondrial respiration, was decreased in mitochondria isolated from DM hearts compared to controls (p<0.0001). Furthermore, the rate of mitochondrial respiration and the increase in carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP)-induced maximal respiration were also decreased with chronic hyperglycemia. Chronic hyperglycemia reduced mitochondrial OXPHOS proteins. Reduced ALDH2 activity was correlated with mitochondrial dysfunction, pathological remodeling and cardiac dysfunction, respectively. Our results suggest that chronic hyperglycemia reduces ALDH2 activity, leading to mitochondrial respiratory dysfunction and consequently cardiac damage and dysfunction.
authors.affiliation: Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI, United States of America.
authors.forename: Vishal R
authors.initials: VR
authors.lastname: Mali
authors.affiliation: Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI, United States of America.
authors.forename: Guodong
authors.initials: G
authors.lastname: Pan
authors.affiliation: Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI, United States of America.
authors.forename: Mandar
authors.initials: M
authors.lastname: Deshpande
authors.affiliation: Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, United States of America.
authors.forename: Rajarajan A
authors.initials: RA
authors.lastname: Thandavarayan
authors.affiliation: Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI, United States of America.
authors.forename: Jiang
authors.initials: J
authors.lastname: Xu
authors.affiliation: Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI, United States of America.
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Yang
authors.affiliation: Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI, United States of America.|Department of Physiology, Wayne State University, Detroit, MI, United States of America.
authors.forename: Suresh S
authors.initials: SS
authors.lastname: Palaniyandi
mesh_terms: D000071396:Aldehyde Dehydrogenase, Mitochondrial / Q000378:metabolism*; D000818:Animals; D006332:Cardiomegaly / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D002908:Chronic Disease; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism / Q000473:pathology; D006943:Hyperglycemia / Q000150:complications* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress; D010101:Oxygen Consumption; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000071396:Aldehyde Dehydrogenase, Mitochondrial; C505112:Aldh2 protein, rat