ABSTRACT
Fatty acid-binding protein 5 (FABP5) is an important member of the FABP family and plays a vital role in the metabolism of fatty acids. However, few studies have examined the role of FABP5 in pathological cardiac remodeling and heart failure. The aim of this study was to explore the role of FABP5 in transverse aortic constriction (TAC)-induced pathological cardiac remodeling and dysfunction in mice. Quantitative RT-PCR (qRT-PCR) and western blotting (WB) analysis showed that the levels of FABP5 mRNA and protein, respectively, were upregulated in hearts of the TAC model. Ten weeks after TAC in FABP5 knockout and wild type control mice, echocardiography, histopathology, qRT-PCR, and WB demonstrated that FABP5 deficiency aggravated cardiac injury (both cardiac hypertrophy and fibrosis) and dysfunction. In addition, transmission electron microscopy, ATP detection, and WB revealed that TAC caused severe impairment to mitochondria in the hearts of FABP5-deficient mice compared with that in control mice. When FABP5 was downregulated by siRNA in primary mouse cardiac fibroblasts, FABP5 silencing increased oxidative stress, reduced mitochondrial respiration, and increased the expression of myofibroblast activation marker genes in response to treatment with transforming growth factor-ß. Our findings demonstrate that FABP5 deficiency aggravates cardiac pathological remodeling and dysfunction by damaging cardiac mitochondrial function.
Subject(s)
Fatty Acid-Binding Proteins/deficiency , Fibroblasts/metabolism , Heart Failure/metabolism , Hypertrophy, Left Ventricular/metabolism , Mitochondria, Heart/metabolism , Myocytes, Cardiac/metabolism , Neoplasm Proteins/deficiency , Ventricular Dysfunction, Left/metabolism , Ventricular Function, Left , Ventricular Remodeling , Adenosine Triphosphate/metabolism , Animals , Cells, Cultured , Disease Models, Animal , Fatty Acid-Binding Proteins/genetics , Fibroblasts/ultrastructure , Fibrosis , Heart Failure/genetics , Heart Failure/pathology , Heart Failure/physiopathology , Hypertrophy, Left Ventricular/genetics , Hypertrophy, Left Ventricular/pathology , Hypertrophy, Left Ventricular/physiopathology , Mice, Inbred C57BL , Mice, Knockout , Mitochondria, Heart/ultrastructure , Myocytes, Cardiac/ultrastructure , Neoplasm Proteins/genetics , Oxidative Stress , Ventricular Dysfunction, Left/genetics , Ventricular Dysfunction, Left/pathology , Ventricular Dysfunction, Left/physiopathologyABSTRACT
Dilated cardiomyopathy (DCM), as one of the common cardiomyopathies, is a disease of the heart muscle; however, the etiology and pathogenesis of DCM were still poorly understood. Nestin has been reported a special marker of stem/progenitor cells in various tissues, and the tissue resident Nestin+ cells could promote the wound healing and tissue remodeling. However, it remains unclear whether Nestin+ cells participate in the protection of cardiomyocytes during the pathogenesis of DCM. Here the model of mice DCM was induced by doxorubicin (DOX) intraperitoneal injection and observed heart failure and ventricular enlargement via echocardiography and histologic analysis, respectively. During DCM pathogenesis, the number of Nestin+ cells showed a significant peak on day 6 after DOX treatment, which then gradually decreases to lower than normal levels after day 30 in the total population of the heart. Furthermore, we found that the isolated increased heart-derived Nestin+ cells are mesenchymal property and could protect DOX-induced HL-1 cells toxicity in vitro by promoting their proliferation and inhibiting their apoptosis. Collectively, our results showed that Nestin+ cells increased during DCM pathogenesis and played an important role in protecting against the DOX-induced HL-1 cells loss via regulating proliferation and apoptosis. Thus, the loss of Nestin+ cells might be an etiology to DCM pathogenesis, and these cells could be a promising candidate cell source for study and treatment of DCM patients.