Abstract
Heart (right) failure is the most frequent cause of death in patients with pulmonary arterial hypertension. Although historically, increased right ventricular afterload has been considered the main contributor to right heart failure in such patients, recent evidence has suggested a potential role of load-independent factors. Here, we tested the hypothesis that resistin–like molecule α (RELMα), which has been implicated in the pathogenesis of vascular remodeling in pulmonary artery hypertension, also contributes to cardiac metabolic remodeling, leading to heart failure. Recombinant RELMα (rRELMα) was generated via a Tet-On expression system in the T-REx 293 cell line. Cultured neonatal rat cardiomyocytes were treated with purified rRELMα for 24 h at a dose of 50 nM. Treated cardiomyocytes exhibited decreased mRNA and protein expression of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) and transcription factors PPARα and ERRα, which regulate mitochondrial fatty acid metabolism, whereas genes that encode for glycolysis-related proteins were significantly upregulated. Cardiomyocytes treated with rRELMα also exhibited a decreased basal respiration, maximal respiration, spare respiratory capacity, ATP-linked OCR, and increased glycolysis, as assessed with a microplate-based cellular respirometry apparatus. Transmission electron microscopy revealed abnormal mitochondrial ultrastructure in cardiomyocytes treated with rRELMα. Our data indicate that RELMα affects cardiac energy metabolism and mitochondrial structure, biogenesis, and function by downregulating the expression of the PGC-1α/PPARα/ERRα axis.
Highlights
Pulmonary arterial hypertension (PAH) is characterized by a chronically increased right ventricular (RV) afterload, which frequently leads to RV failure and untimely death [1, 2]
We found significant decrease in C-4 to C-12 straight chain of acylcoA dehydrogenases (ACADM) and C-2 to C-3 short chain of acyl-coA dehydrogenases (ACADS) gene involved in fatty acid oxidation
Because the RV tissue from rats and humans with severe PAH is characterized by downregulation of proliferatoractivated receptor gamma coactivator 1-α (PGC-1α), as well as multiple downstream fatty acid oxidation genes, we hypothesized that resistin-like molecule α (RELMα) could affect cellular metabolism via downregulation of PGC-1α
Summary
Pulmonary arterial hypertension (PAH) is characterized by a chronically increased right ventricular (RV) afterload, which frequently leads to RV failure and untimely death [1, 2]. Decreased myocardial expression of the transcription factor peroxisome proliferatoractivated receptor gamma coactivator 1-α (PGC-1α), a key factor in regulating mitochondrial biogenesis pathways, has been reported in experimental models of heart failure [10,11,12] It is significantly downregulated in the RVs of rats with severe PAH secondary to SU5416/hypoxia exposure, as well as in RV tissue from patients with severe PAH [13]. Rodent isoform of resistin RELMα, known as hypoxia induced mitogenic factor (HIMF), attenuates adenosine triphosphate (ATP)-linked OCR, fatty acid oxidation (FAO) and partially increases glycolytic oxidation as compensatory mechanism in NRCMs. Mechanistically, RELMα attenuates PGC1α/PPARα/ERRα signaling axis which leads to down regulation of mitochondrial biogenesis genes (TFAM, TOP1MT, POLG2, and POLRMT), FAO metabolic genes (LCAD, VLCAD, ACADM, ACADS) as well as mitochondrial fatty acid (FA) transporter genes (Cpt-1a, Cpt-1b). Persistent decrease in FAO and ATP-linked OCR leads to mitochondrial dysfunction which affects cardiac bioenergetics, cardiac dysfunction
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