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. 2019 Jan 8;2019:5408289.
doi: 10.1155/2019/5408289. eCollection 2019.

Phosphocreatine Attenuates Isoproterenol-Induced Cardiac Fibrosis and Cardiomyocyte Apoptosis

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Free PMC article

Phosphocreatine Attenuates Isoproterenol-Induced Cardiac Fibrosis and Cardiomyocyte Apoptosis

Hui Dai et al. Biomed Res Int. .
Free PMC article

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.

Figures

Figure 1
Figure 1
PCr inhibited ISO-induced cardiac fibrosis. (a-b) Picrosirius red staining and the CVF of each group. (c-d) Laminin level between each group. (e–h) Western blots and quantification of collagen I, collagen III, TGF-β1, and α-SMA protein expression in left ventricular tissues. ∗P<0.05, ∗∗P<0.01, and ∗∗∗P<0.001, versus the ISO group, n=8 per group. Scale bar=50 μm.
Figure 2
Figure 2
PCr prevented ISO-induced cardiac fibrosis through MAPK and NF-κB pathway. (a–c) The expression of p-ERK, p-JNK, and p-P38 was analyzed by Western blotting. (d) NF-κB in nuclear extraction was analyzed. ∗P<0.05, ∗∗P<0.01, and ∗∗∗P<0.001, versus the ISO group, n=8 per group.
Figure 3
Figure 3
PCr regulated the expression of MMP-9 and TIMP-1. (a) Western blot of protein expression of MMP-9. (b) Expression of TIMP-1 protein. P<0.05; ∗∗P<0.01, versus the ISO group, n=8 per group.
Figure 4
Figure 4
PCr decreased cardiomyocyte apoptosis. (a) Results of TUNEL staining. (b) The number of apoptotic cells per field. (c–e) Western blots of Bcl-2, Bax, and CASP-3 protein. P<0.05, ∗∗P<0.01, and ∗∗∗P<0.001, versus the ISO group, n=8 per group. Scale bar=50 μm.

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