Apolipoprotein A1 regulates coenzyme Q10 absorption, mitochondrial function, and infarct size in a mouse model of myocardial infarction.
HDL and apolipoprotein A1 (apoA1) concentrations inversely correlate with risk of death from ischemic heart disease; however, the role of apoA1 in the myocardial response to ischemia has not been well defined. To test whether apoA1, the primary HDL apolipoprotein, has an acute anti-inflammatory role in ischemic heart disease, we induced myocardial infarction via direct left anterior descending coronary artery ligation in apoA1 null (apoA1(-/-)) and apoA1 heterozygous (apoA1(+/-)) mice. We observed that apoA1(+/-) and apoA1(-/-) mice had a 52% and 125% increase in infarct size as a percentage of area at risk, respectively, compared with wild-type (WT) C57BL/6 mice. Mitochondrial oxidation contributes to tissue damage in ischemia-reperfusion injury. A substantial defect was present at baseline in the electron transport chain of cardiac myocytes from apoA1(-/-) mice localized to the coenzyme Q (CoQ) pool with impaired electron transfer (67% decrease) from complex II to complex III. Administration of coenzyme Q10 (CoQ10) to apoA1 null mice normalized the cardiac mitochondrial CoQ pool and reduced infarct size to that observed in WT mice. CoQ10 administration did not significantly alter infarct size in WT mice. These data identify CoQ pool content leading to impaired mitochondrial function as major contributors to infarct size in the setting of low HDL/apoA1. These data suggest a previously unappreciated mechanism for myocardial stunning, cardiac dysfunction, and muscle pain associated with low HDL and low apoA1 concentrations that can be corrected by CoQ10 supplementation and suggest populations of patients that may benefit particularly from CoQ10 supplementation.
Department of Anesthesia, Cleveland Clinic, Cleveland, OH.
Alisher R
AR
Dadabayev
Department of Cardiology, School of Medicine, Virginia Commonwealth University, McGuire Veterans Affairs Medical Center, Richmond, VA Department of Cardiology, Third Affiliated Hospital, Xinxiang Medical University, Xinxiang, China.
Guotian
G
Yin
Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
Calivarathan
C
Latchoumycandane
Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
Thomas M
TM
McIntyre
Department of Cardiology, School of Medicine, Virginia Commonwealth University, McGuire Veterans Affairs Medical Center, Richmond, VA.
Edward J
EJ
Lesnefsky
Department of Integrated Medical Sciences, Northeast Ohio Medical University, Rootstown, OH; and Summa Cardiovascular Institute, Summa Health System, Akron, OH mpenn2@neomed.edu.
Marc S
MS
Penn
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016632:Apolipoprotein A-I / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D019587:Dietary Supplements; D004195:Disease Models, Animal; D004579:Electron Transport / Q000187:drug effects; D042963:Electron Transport Complex II / Q000737:chemistry / Q000378:metabolism; D014450:Electron Transport Complex III / Q000737:chemistry / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D052456:Hypoalphalipoproteinemias / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D007408:Intestinal Absorption; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009203:Myocardial Infarction / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D014018:Tissue Distribution; D014451:Ubiquinone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use
D000975:Antioxidants; D016632:Apolipoprotein A-I; D002316:Cardiotonic Agents; D014451:Ubiquinone; D042963:Electron Transport Complex II; D014450:Electron Transport Complex III; C024989:coenzyme Q10