TY - JOUR
T1 - Alteration of cardiolipin biosynthesis and remodeling in single right ventricle congenital heart disease
AU - Garcia, Anastacia M.
AU - McPhaul, Jessica C.
AU - Sparagna, Genevieve C.
AU - Jeffrey, Danielle A.
AU - Jonscher, Raleigh
AU - Patel, Sonali S.
AU - Sucharov, Carmen C.
AU - Stauffer, Brian L.
AU - Miyamoto, Shelley D.
AU - Chatfield, Kathryn C.
N1 - Funding Information:
This work was supported by National Heart, Lung, and Blood Institute Grants R01-HL-126928 (to S. D. Miyamoto), R01-HL-107715 (to B. L.
Funding Information:
Stauffer), and R01-HL-126928-03S1 (to A. M. Garcia and S. D. Miyamoto); the Addison Scott Memorial Fund; the Boedecker Foundation; the Nair Family; the Rose Community Foundation; the Jack Cooper Millisor Chair in Pediatric Heart Disease; and Colorado Clinical and Translational Sciences Institute Child and Maternal Health Pilot Grant CMH-M-18-34 (to A. M. Garcia), supported in part by Colorado Clinical and Translational Science Award Grants UL1-TR002535, KL2-TR002534, and TL1-TR002533 from National Center for Advancing Translational Sciences.
Publisher Copyright:
Copyright © 2020 the American Physiological Society
PY - 2020/4
Y1 - 2020/4
N2 - Despite advances in both medical and surgical therapies, individuals with single ventricle heart disease (SV) remain at high risk for the development of heart failure (HF). However, the molecular mechanisms underlying remodeling and eventual HF in patients with SV are poorly characterized. Cardiolipin (CL), an inner mitochondrial membrane phospholipid, is critical for proper mitochondrial function, and abnormalities in CL content and composition are known in various cardiovascular disease etiologies. The purpose of this study was to investigate myocardial CL content and composition in failing and nonfailing single right ventricle (RV) samples compared with normal control RV samples, to assess mRNA expression of CL biosynthetic and remodeling enzymes, and to quantitate relative mitochondrial copy number. A cross-sectional analysis of RV myocardial tissue from 22 failing SV (SVHF), 9 nonfailing SV (SVNF), and 10 biventricular control samples (BVNF) was performed. Expression of enzymes involved in CL biosynthesis and remodeling were analyzed using RT-qPCR and relative mitochondrial DNA copy number determined by qPCR. Normal phase high-pressure liquid chromatography coupled to electrospray ionization mass spectrometry was used to quantitate total and specific CL species. While mitochondrial copy number was not significantly different between groups, total CL content was significantly lower in SVHF myocardium compared with BVNF controls. Despite having lower total CL content however, the relative percentage of the major tetralinoleoyl CL species is preserved in SVHF samples relative to BVNF controls. Correspondingly, expression of enzymes involved in CL biosynthesis and remodeling were upregulated in SVHF samples when compared with both SVNF samples and BVNF controls. NEW & NOTEWORTHY The mechanisms underlying heart failure in the single ventricle (SV) congenital heart disease population are largely unknown. In this study we identify alterations in cardiac cardiolipin metabolism, composition, and content in children with SV heart disease. These findings suggest that cardiolipin could be a novel therapeutic target in this unique population of patients.
AB - Despite advances in both medical and surgical therapies, individuals with single ventricle heart disease (SV) remain at high risk for the development of heart failure (HF). However, the molecular mechanisms underlying remodeling and eventual HF in patients with SV are poorly characterized. Cardiolipin (CL), an inner mitochondrial membrane phospholipid, is critical for proper mitochondrial function, and abnormalities in CL content and composition are known in various cardiovascular disease etiologies. The purpose of this study was to investigate myocardial CL content and composition in failing and nonfailing single right ventricle (RV) samples compared with normal control RV samples, to assess mRNA expression of CL biosynthetic and remodeling enzymes, and to quantitate relative mitochondrial copy number. A cross-sectional analysis of RV myocardial tissue from 22 failing SV (SVHF), 9 nonfailing SV (SVNF), and 10 biventricular control samples (BVNF) was performed. Expression of enzymes involved in CL biosynthesis and remodeling were analyzed using RT-qPCR and relative mitochondrial DNA copy number determined by qPCR. Normal phase high-pressure liquid chromatography coupled to electrospray ionization mass spectrometry was used to quantitate total and specific CL species. While mitochondrial copy number was not significantly different between groups, total CL content was significantly lower in SVHF myocardium compared with BVNF controls. Despite having lower total CL content however, the relative percentage of the major tetralinoleoyl CL species is preserved in SVHF samples relative to BVNF controls. Correspondingly, expression of enzymes involved in CL biosynthesis and remodeling were upregulated in SVHF samples when compared with both SVNF samples and BVNF controls. NEW & NOTEWORTHY The mechanisms underlying heart failure in the single ventricle (SV) congenital heart disease population are largely unknown. In this study we identify alterations in cardiac cardiolipin metabolism, composition, and content in children with SV heart disease. These findings suggest that cardiolipin could be a novel therapeutic target in this unique population of patients.
KW - Cardiolipin
KW - Hypoplastic left heart syndrome
KW - Mitochondria
KW - Single ventricle congenital heart disease
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U2 - 10.1152/ajpheart.00494.2019
DO - 10.1152/ajpheart.00494.2019
M3 - Article
C2 - 32056460
AN - SCOPUS:85082147609
SN - 0363-6135
VL - 318
SP - H787-H800
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 4
ER -