Takehiro Yamaguchi1, Yasukatsu Izumi2, Yasuhiro Nakamura3, Takanori Yamazaki1, Masayuki Shiota4, Soichi Sano1, Masako Tanaka5, Mayuko Osada-Oka6, Kenei Shimada1, Katuyuki Miura5, Minoru Yoshiyama1, Hiroshi Iwao7. 1. Department of Cardiovascular Medicine, Osaka City University Medical School, Osaka, Japan. 2. Department of Pharmacology, Osaka City University Medical School, Osaka, Japan. Electronic address: izumi@msic.med.osaka-cu.ac.jp. 3. Department of Cardiovascular Medicine, Osaka City University Medical School, Osaka, Japan; Department of Cardiology, Izumi Municipal Hospital, Izumi, Japan. 4. Department of Pharmacology, Osaka City University Medical School, Osaka, Japan. 5. Department of Pharmacology, Osaka City University Medical School, Osaka, Japan; Applied Pharmacology and Therapeutics, Osaka City University Medical School, Osaka, Japan. 6. Food Hygiene and Environmental Health Division of Applied Life Science, Kyoto Prefectural University, Kyoto, Japan. 7. Department of Pharmacology, Osaka City University Medical School, Osaka, Japan; Department of Education, Shitennoji University, Habikino, Japan.
Abstract
BACKGROUND: Remote ischemic conditioning (RIC) by repeated treatment of transient limb ischemia is a clinically applicable method for protecting the heart against injury at the time of reperfusion. In this study, we investigated the effects of repeated RIC on cardiac dysfunction after myocardial infarction (MI). METHODS AND RESULTS: At 4weeks after MI, rats were separated into the untreated (UT) group or the RIC-treated group. RIC treatment was performed by 5cycles of 5min of bilateral hindlimb ischemia and 5min of reperfusion once a day for 4weeks. Despite comparable MI size, left ventricular (LV) ejection fraction (LVEF) was significantly improved in the RIC group compared with the UT group. Furthermore, the LVEF in the RIC group was improved, although not significantly, after treatment. RIC treatment also prevented the deterioration of LV diastolic function. MI-induced LV interstitial fibrosis in the boundary region and oxidant stress were significantly attenuated by RIC treatment. MicroRNA-29a (miR-29a), a key regulator of tissue fibrosis, was highly expressed in the exosomes and the marginal area of the RIC group. Even in the differentiated C2C12-derived exosomes, miR-29a expression was significantly increased under hypoxic condition. As well as miR-29a, insulin-like growth factor 1 receptor (IGF-1R) was highly expressed both in the exosomes and remote non-infarcted myocardium of the RIC group. IGF-1R expression was also increased in the C2C12-derived exosomes under hypoxic conditions. CONCLUSIONS: Repeated RIC reduces adverse LV remodeling and oxidative stress by MI. Exosome-mediated intercellular communication may contribute to the beneficial effect of RIC treatment.
BACKGROUND: Remote ischemic conditioning (RIC) by repeated treatment of transient limb ischemia is a clinically applicable method for protecting the heart against injury at the time of reperfusion. In this study, we investigated the effects of repeated RIC on cardiac dysfunction after myocardial infarction (MI). METHODS AND RESULTS: At 4weeks after MI, rats were separated into the untreated (UT) group or the RIC-treated group. RIC treatment was performed by 5cycles of 5min of bilateral hindlimb ischemia and 5min of reperfusion once a day for 4weeks. Despite comparable MI size, left ventricular (LV) ejection fraction (LVEF) was significantly improved in the RIC group compared with the UT group. Furthermore, the LVEF in the RIC group was improved, although not significantly, after treatment. RIC treatment also prevented the deterioration of LV diastolic function. MI-induced LV interstitial fibrosis in the boundary region and oxidant stress were significantly attenuated by RIC treatment. MicroRNA-29a (miR-29a), a key regulator of tissue fibrosis, was highly expressed in the exosomes and the marginal area of the RIC group. Even in the differentiated C2C12-derived exosomes, miR-29a expression was significantly increased under hypoxic condition. As well as miR-29a, insulin-like growth factor 1 receptor (IGF-1R) was highly expressed both in the exosomes and remote non-infarcted myocardium of the RIC group. IGF-1R expression was also increased in the C2C12-derived exosomes under hypoxic conditions. CONCLUSIONS: Repeated RIC reduces adverse LV remodeling and oxidative stress by MI. Exosome-mediated intercellular communication may contribute to the beneficial effect of RIC treatment.