Cardiolipin biosynthesis and remodeling enzymes are altered during development of heart failure.
Cardiolipin (CL) is responsible for modulation of activities of various enzymes involved in oxidative phosphorylation. Although energy production decreases in heart failure (HF), regulation of cardiolipin during HF development is unknown. Enzymes involved in cardiac cardiolipin synthesis and remodeling were studied in spontaneously hypertensive HF (SHHF) rats, explanted hearts from human HF patients, and nonfailing Sprague Dawley (SD) rats. The biosynthetic enzymes cytidinediphosphatediacylglycerol synthetase (CDS), phosphatidylglycerolphosphate synthase (PGPS) and cardiolipin synthase (CLS) were investigated. Mitochondrial CDS activity and CDS-1 mRNA increased in HF whereas CDS-2 mRNA in SHHF and humans, not in SD rats, decreased. PGPS activity, but not mRNA, increased in SHHF. CLS activity and mRNA decreased in SHHF, but mRNA was not significantly altered in humans. Cardiolipin remodeling enzymes, monolysocardiolipin acyltransferase (MLCL AT) and tafazzin, showed variable changes during HF. MLCL AT activity increased in SHHF. Tafazzin mRNA decreased in SHHF and human HF, but not in SD rats. The gene expression of acyl-CoA: lysocardiolipin acyltransferase-1, an endoplasmic reticulum MLCL AT, remained unaltered in SHHF rats. The results provide mechanisms whereby both cardiolipin biosynthesis and remodeling are altered during HF. Increases in CDS-1, PGPS, and MLCL AT suggest compensatory mechanisms during the development of HF. Human and SD data imply that similar trends may occur in human HF, but not during nonpathological aging, consistent with previous cardiolipin studies.
Saini-Chohan
Harjot K
HK
Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
Holmes
Michael G
MG
Chicco
Adam J
AJ
Taylor
William A
WA
Moore
Russell L
RL
McCune
Sylvia A
SA
Hickson-Bick
Diane L
DL
Hatch
Grant M
GM
Sparagna
Genevieve C
GC
D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism; D000375:Aging; D000818:Animals; D001835:Body Weight; D002308:Cardiolipins / Q000096:biosynthesis* / Q000737:chemistry; D002311:Cardiomyopathy, Dilated / Q000201:enzymology; D003567:Cytidine Diphosphate Diglycerides / Q000096:biosynthesis; D002798:Diacylglycerol Cholinephosphotransferase / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006333:Heart Failure / Q000201:enzymology* / Q000473:pathology*; D006352:Heart Ventricles; D006801:Humans; D006973:Hypertension; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology / Q000473:pathology*; D008246:Lysophospholipids / Q000096:biosynthesis; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008929:Mitochondria, Heart / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010712:Phosphatidic Acids / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000235:genetics; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics / Q000378:metabolism
D002308:Cardiolipins; D003567:Cytidine Diphosphate Diglycerides; D008246:Lysophospholipids; D008565:Membrane Proteins; D010712:Phosphatidic Acids; D014157:Transcription Factors; C067188:monolysocardiolipin; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; D017855:Transferases (Other Substituted Phosphate Groups); C100091:cardiolipin synthetase; D002798:Diacylglycerol Cholinephosphotransferase; C020676:CDP-diacylglycerol-glycerol-3-phosphate 3-phosphatidyltransferase