Abstract
The present study was designed to further explore the role and the underlying molecular mechanism of phosphocreatine (PCr) for cardiac fibrosis in vivo. Isoproterenol (ISO) was used to induce cardiac fibrosis in rats. PCr administration ameliorated fibrosis by reducing collagen accumulation and fibrosis-related signals, including transforming growth factor beta 1 (TGF-β1), alpha smooth muscle actin (α-SMA), collagen type I, and collagen type III. Mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) signaling pathways, including p38, extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p65, were highly activated by ISO and blocked by PCr. Moreover, PCr decreased ISO-induced matrix metalloproteinase-9 (MMP-9) and increased the tissue inhibitor of metalloproteinase-1 (TIMP-1) expression. Furthermore, PCr suppressed cardiomyocyte apoptosis induced by ISO, as shown by downregulated expression of the proapoptotic caspase-3, Bax, and upregulated expression of the antiapoptotic Bcl-2. Taken together, PCr can be an effective agent for preventing cardiac fibrosis and cardiomyocyte apoptosis.
Highlights
Cardiac fibrosis is a common pathological change in various heart diseases that develops to a certain stage and is characterized by excessive extracellular matrix (ECM) deposition [1]
We demonstrated that PCr suppressed cardiac fibrosis in rat cardiomyocytes through modulation of Mitogen-activated protein kinases (MAPKs) and NF-κB pathways [13]
The left ventricular end-diastolic dimension (LVDd), left ventricular endsystolic dimension (LVDs), ejection fraction (EF), and fractional shortening (FS) were lower in the ISO group than those in the control group, and PCr improved the LVDd, LVDs, EF, and FS slightly
Summary
Cardiac fibrosis is a common pathological change in various heart diseases that develops to a certain stage and is characterized by excessive extracellular matrix (ECM) deposition [1]. Cardiac fibrosis can result in diastolic dysfunction and arrhythmia, leading to heart failure [2]. The development of fibrosis depends on upregulation of MMPs and downregulation of TIMPs, activation of profibrotic mediators, differentiation of fibroblasts into myofibroblasts, and endothelial-to-mesenchymal transition (EndMT) [3,4,5]. Many mediators induce the transformation of fibroblasts into myofibroblasts, which is characterized by expression of α-SMA, proliferation, migration, and release of proinflammatory signals, and increased production of ECM remodeling proteins. Inflammatory factors, cytokines, and signaling pathways can interact with one another to form a complex network to promote the continuous development of cardiac fibrosis. A growing body of evidence has focused on slowing, preventing, or even reversing the progress of cardiac fibrosis; there have been few effective therapies to date
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