Myocardial protection from ischemia/reperfusion injury by endogenous and exogenous HGF
Teruya Nakamura, Shinya Mizuno, Kunio Matsumoto, Yoshiki Sawa, Hikaru Matsuda, Toshikazu Nakamura
Teruya Nakamura, Shinya Mizuno, Kunio Matsumoto, Yoshiki Sawa, Hikaru Matsuda, Toshikazu Nakamura
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Myocardial protection from ischemia/reperfusion injury by endogenous and exogenous HGF

Abstract

Using a rat model of ischemia/reperfusion injury, we demonstrate here that HGF is cardioprotective due to its antiapoptotic effect on cardiomyocytes. Following transient myocardial ischemia and reperfusion, c-Met/HGF receptor expression rapidly increased in the ischemic myocardium, an event accompanied by a dramatic increase in plasma HGF levels in the infarcted rats. When endogenous HGF was neutralized with a specific antibody, the number of myocyte cell deaths increased markedly, the infarct area expanded, and the mortality increased to 50%, as compared with a control group in which there was no mortality. Plasma from the myocardial infarcted rats had cardioprotective effects on primary cultured cardiomyocytes, but these effects were significantly diminished by neutralizing HGF. In contrast, recombinant HGF administration reduced the size of infarct area and improved cardiac function by suppressing apoptosis in cardiomyocytes. HGF rapidly augmented Bcl-xL expression in injured cardiomyocytes both in vitro and in vivo. As apoptosis of cardiomyocytes is one of the major contributors to the pathogenesis in subjects with ischemia/reperfusion injury, prevention of apoptosis may prove to be a reasonable therapeutic strategy. Supplements of HGF, an endogenous cardioprotective factor, may be found clinically suitable in treating subjects with myocardial infarction.

Authors

Teruya Nakamura, Shinya Mizuno, Kunio Matsumoto, Yoshiki Sawa, Hikaru Matsuda, Toshikazu Nakamura

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Changes in pathophysiology and HGF/c-Met expression in rats with ischemi...
Changes in pathophysiology and HGF/c-Met expression in rats with ischemia/reperfusion injury. (a–d) Histopathology of the heart. At 6 hours after treatment, infiltration with inflammatory cells was seen in the LVFW (a, b). At 24 hours after ischemia/reperfusion, a more diffuse infiltration of inflammatory cells was evident (c), and the infarct lesion had expanded widely at 48 hours (d) Bars: a, c, and d, 200 μm; b, 50 μm. (e) Change in CPK activity in sera. I/R, ischemia/reperfusion injury. AP < 0.001, BP < 0.01, CP < 0.05. (f) Plasma HGF levels determined by ELISA. AP < 0.001, BP < 0.01, CP < 0.05. (g) Change in c-Met mRNA expression in myocardium, as determined by quantitative RT-PCR. AP < 0.001, BP < 0.01, CP < 0.05 compared with IVS; DP < 0.001, EP < 0.01 compared with sham LV. (h–m) Immunohistochemical findings for c-Met. (h–k) Double immunohistochemistry for α-sarcomeric actin and c-Met in the heart resected 48 hours after reperfusion. Photographs of the LVFW (h, i) and IVS (j, k) of a section are shown. Red (h, j) and green (i, k) fluorescence, respectively, indicate α-sarcomeric actin and c-Met labeling. (l and m) Immunostaining for c-Met in the sham-operated myocardium (l) and the border region between infarcted and noninfarcted area (m). To detect background staining, anti–c-Met antibody was preabsorbed with antigenic synthetic peptide in a serial section (inset in m). Bars: 100 μm.