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. 2009 Aug;50(8):1600-8.
doi: 10.1194/jlr.M800561-JLR200. Epub 2008 Nov 10.

Cardiolipin biosynthesis and remodeling enzymes are altered during development of heart failure

Harjot K Saini-Chohan  1 , Michael G Holmes, Adam J Chicco, William A Taylor, Russell L Moore, Sylvia A McCune, Diane L Hickson-Bick, Grant M Hatch, Genevieve C Sparagna
Affiliations

Cardiolipin biosynthesis and remodeling enzymes are altered during development of heart failure

Harjot K Saini-Chohan et al. J Lipid Res. 2009 Aug.

Abstract

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.

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Figures

Fig. 1.
Fig. 1.
Cytidinediphosphatediacylglycerol synthetase (CDS) activity and real time PCR from LV tissue. (A) Activity in mitochondrial fraction from SHHF rats; (B) Activity in microsomal endoplasmic reticulum fraction from SHHF rats; (C) CDS-1 mRNA from SHHF rats; (D) CDS-2 mRNA from SHHF rats; (E) CDS-2 mRNA in human nonfailing (NF) or idiopathic dilated cardiomyopathy (IDC); and (F) CDS-2 mRNA from Sprague Dawley rats. All PCR data is expressed as mean ± SEM with the young rats or NF humans as 100%. N = 4 (rats) and 8 (humans) per group. *P < 0.05 vs. 2 month SHHF rats or NF humans. SHHF, spontaneously hypertensive heart failure.
Fig. 2.
Fig. 2.
Phosphatidylglycerolphosphate synthase (PGPS) activity and real time PCR from LV tissue. (A) Activity from SHHF rats and (B) mRNA from SHHF rats. PCR data is expressed as mean ± SEM with the young rats as 100%. N = 4, *P < 0.05 vs. 2-month SHHF rats. SHHF, spontaneously hypertensive heart failure.
Fig. 3.
Fig. 3.
CL synthase (CLS) activity and real time PCR from LV tissue. (A) Activity from SHHF rats; (B) CLS mRNA from SHHF rats; and (C) CLS mRNA in human nonfailing (NF) or idiopathic dilated cardiomyopathy (IDC). All PCR data is expressed as mean ± SEM with the young rats or NF humans as 100%. N = 4 (rats) and 8 (humans) per group. *P < 0.05 vs. 2-month SHHF rats or NF humans. SHHF, spontaneously hypertensive heart failure.
Fig. 4.
Fig. 4.
CL remodeling enzyme activity and real time PCR from LV tissue. (A) Activity of monolysocardiolipin acyltransferase (MLCL AT) in SHHF rats; (B) Acyl-CoA: lysocardiolipin acyltransferase 1 (ALCAT1) mRNA from SHHF rats; (C) Tafazzin (TAZ) mRNA from SHHF rats; (D) TAZ mRNA in human nonfailing (NF) or idiopathic dilated cardiomyopathy (IDC); and (E) TAZ mRNA from Sprague Dawley rats. All PCR data is expressed as mean ± SEM with the young rats or NF humans as 100%. N = 4 (rats) and 8 (humans) per group. *P 0.05 vs. 2-month SHHF rats or NF humans. SHHF, spontaneously hypertensive heart failure.
Fig. 5.
Fig. 5.
Schematic showing changes in CL biosynthesis and remodeling enzymes in heart failure. Small arrows indicate general changes to the enzyme in HF in the present study. CDP-DAG, cytidinediphosphate diacylglycerol; CDS, cytidinediphosphatediacylglycerol synthetase ;CL, cardiolipin; (18:2)4CL, tetralinoleoyl CL; CLS, cardiolipin synthase; MLCL, monolysocardiolipin; MLCL AT, MLCL acyl transferase; PA phosphatidic acid; PG, phosphatidyl glycerol; PGP, phosphatidylglycerolphosphate ; PGPS, PGP synthase ;TAZ, tafazzin.
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