Increased expression of fatty-acid and calcium metabolism genes in failing human heart.
BACKGROUND
Heart failure (HF) involves alterations in metabolism, but little is known about cardiomyopathy-(CM)-specific or diabetes-independent alterations in gene expression of proteins involved in fatty-acid (FA) uptake and oxidation or in calcium-(Ca(2+))-handling in the human heart.


METHODS
RT-qPCR was used to quantify mRNA expression and immunoblotting to confirm protein expression in left-ventricular myocardium from patients with HF (n = 36) without diabetes mellitus of ischaemic (ICM, n = 16) or dilated (DCM, n = 20) cardiomyopathy aetiology, and non-diseased donors (CTL, n = 6).


RESULTS
Significant increases in mRNA of genes regulating FA uptake (CD36) and intracellular transport (Heart-FA-Binding Protein (HFABP)) were observed in HF patients vs CTL. Significance was maintained in DCM and confirmed at protein level, but not in ICM. mRNA was higher in DCM than ICM for peroxisome-proliferator-activated-receptor-alpha (PPARA), PPAR-gamma coactivator-1-alpha (PGC1A) and CD36, and confirmed at the protein level for PPARA and CD36. Transcript and protein expression of Ca(2+)-handling genes (Two-Pore-Channel 1 (TPCN1), Two-Pore-Channel 2 (TPCN2), and Inositol 1,4,5-triphosphate Receptor type-1 (IP3R1)) increased in HF patients relative to CTL. Increases remained significant for TPCN2 in all groups but for TPCN1 only in DCM. There were correlations between FA metabolism and Ca(2+)-handling genes expression. In ICM there were six correlations, all distinct from those found in CTL. In DCM there were also six (all also different from those found in CTL): three were common to and three distinct from ICM.


CONCLUSIONS
DCM-specific increases were found in expression of several genes that regulate FA metabolism, which might help in the design of aetiology-specific metabolic therapies in HF. Ca(2+)-handling genes TPCN1 and TPCN2 also showed increased expression in HF, while HF- and CM-specific positive correlations were found among several FA and Ca(2+)-handling genes.
Laboratory of Cellular and Molecular Cardiology, Santiago Institute of Biomedical Research (IDIS), University of Santiago de Compostela Clinical Hospital (CHUS), Santiago de Compostela, Spain.
Vanessa
V
García-Rúa
Manuel Francisco
MF
Otero
Pamela Virginia
PV
Lear
Diego
D
Rodríguez-Penas
Sandra
S
Feijóo-Bandín
Teresa
T
Noguera-Moreno
Manuel
M
Calaza
María
M
Álvarez-Barredo
Ana
A
Mosquera-Leal
John
J
Parrington
Josep
J
Brugada
Manuel
M
Portolés
Miguel
M
Rivera
José Ramón
JR
González-Juanatey
Francisca
F
Lago
D018955:CD36 Antigens / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D016022:Case-Control Studies; D017931:DNA Primers / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D006352:Heart Ventricles / Q000166:cytology; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D047493:PPAR alpha / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D014157:Transcription Factors / Q000378:metabolism; D000097903:Two-Pore Channels
D018955:CD36 Antigens; D002118:Calcium; D015220:Calcium Channels; D017931:DNA Primers; D005227:Fatty Acids; D006360:Heat-Shock Proteins; D047493:PPAR alpha; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger; D014157:Transcription Factors; C486497:PPARGC1A protein, human; C407357:TPCN1 protein, human; D000097903:Two-Pore Channels; C530224:TPCN2 protein, human