Abstract
BackgroundHeart 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-(Ca2+)-handling in the human heart.MethodsRT-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).ResultsSignificant 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 Ca2+-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 Ca2+-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.ConclusionDCM-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. Ca2+-handling genes TPCN1 and TPCN2 also showed increased expression in HF, while HF- and CM-specific positive correlations were found among several FA and Ca2+-handling genes.
Highlights
Human heart failure (HF) has been described as a hyperadrenergic state leading to increased plasma levels of free fatty acids (FFA), which in turn cause a range of metabolic dysfunctions including aberrant FA uptake and oxidation in the myocardium [1]
Analysis by western blot of the protein levels of CD36 confirmed that expression of this protein was significantly higher (p = 0.013, Mann-Whitney test) in the cardiac tissue of patients with Heart failure (HF) of dilated aetiology (DCM; n = 7) than in those of ischaemic aetiology (ICM; n = 7) (Fig. 1)
Heart Fatty-Acid-Binding Protein (HFABP) protein levels analysis by western blot confirmed that the expression of this protein was significantly increased only in HF patients of dilated aetiology (n = 6 DCM vs n = 3 CTL, p = 0.031) (Fig. 1)
Summary
Human heart failure (HF) has been described as a hyperadrenergic state leading to increased plasma levels of free fatty acids (FFA), which in turn cause a range of metabolic dysfunctions including aberrant FA uptake and oxidation in the myocardium [1]. One consistent finding in HF patients is an increase in plasma levels of Heart Fatty-Acid-Binding Protein (HFABP) which can be substantial [8,9,10]. In light of its role in intracellular transport to the mitochondria where FAs undergo b-oxidation [11], it is of note that expression levels of HFABP within the myocardium have not previously been studied in HF patients. 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-(Ca2+)-handling in the human heart
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