Elsevier

International Journal of Cardiology

Volume 178, 15 January 2015, Pages 239-246
International Journal of Cardiology

Repeated remote ischemic conditioning attenuates left ventricular remodeling via exosome-mediated intercellular communication on chronic heart failure after myocardial infarction

https://doi.org/10.1016/j.ijcard.2014.10.144Get rights and content

Highlights

  • Repeated remote ischemic conditioning (RIC) is useful for chronic heart failure (HF).

  • RIC increases the total amount of proteins secreted from exosomes.

  • RIC prevents cardiac dysfunction via exosome-mediated intercellular communication.

  • RIC is easy to perform and may be well tolerated to the patients with chronic HF.

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 4 weeks after MI, rats were separated into the untreated (UT) group or the RIC-treated group. RIC treatment was performed by 5 cycles of 5 min of bilateral hindlimb ischemia and 5 min of reperfusion once a day for 4 weeks. 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.

Introduction

Chronic heart failure (CHF) is a clinical syndrome representing the end-stage of a number of different cardiac diseases. It causes exercise intolerance, impairs quality of life, and has been associated with high morbidity and mortality. Although the existing pharmacological therapies, such as inhibitors of the renin–angiotensin–aldosterone system and β-adrenoreceptor blockers improved outcomes in CHF [1], [2], [3], [4], they are still not optimal and cannot fully prevent progressive cardiac remodeling and dysfunction. Recently, several non-pharmacological therapies such as cardiac rehabilitation and ventilatory support have been developed [5], [6]. However, these therapies are associated with tolerability issues, and not all CHF patients benefit from them. Therefore, there is a need to develop a novel therapy that is easy to perform and is well tolerated.

The cardioprotective effect of remote ischemic preconditioning was originally reported by Przykelenk et al. [7]. They reported that ischemic preconditioning in the left circumflex coronary artery attenuated ischemia-reperfusion (IR) injury by subsequent occlusion of the left anterior descending coronary artery (LAD). Thereafter, some reports have shown that ischemic preconditioning [8], [9] and postconditioning [10], [11] of the extremities can protect the heart from IR injury. Thus, remote ischemic conditioning (RIC) may be one of the therapeutic strategies for protecting organs or tissue against IR injury. Briefly repeated non-lethal ischemia and reperfusion of a remote organ or tissue increase heart tolerability to acute IR injury. Although various studies supported the beneficial effect of RIC against acute myocardial infarction (MI), it is still unclear whether RIC is beneficial for CHF.

In this study, we hypothesized that the efficacy of RIC can expand not only to IR injury in the acute phase of MI but to left ventricular (LV) dysfunction in the chronic phase of MI. Our results showed that RIC treatment improved LV dysfunction and attenuated LV interstitial fibrosis in an experimental CHF model. These results may have clinical implications for the treatment of patients with evolving LV dysfunction.

Section snippets

Animals and experimental design

All procedures were performed in accordance to Osaka City University animal care guidelines, which conform to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996). The 8-week-old male Wistar rats weighing 260–290 g were purchased from CLEA Japan, Inc (Osaka, Japan).

The rats were intubated and were under mechanical ventilation with adequate anesthesia by pentobarbital (50 mg·kg 1, intraperitoneally). Then,

Effects of RIC treatment on hemodynamic status and body weight

Laser Doppler blood flow measurement was performed to confirm successful transient hindlimb ischemia by RIC treatment (Fig. 1B). During RIC treatment, blood flow in the hindlimb was diminished. Since the tourniquet was released, blood flow was recovered; moreover increased. Despite the increase of peripheral blood flow after RIC treatment, there was no significant difference in hemodynamic status such as BP and HR among the groups (Fig. 1C). Thus, RIC does not affect hemodynamic status.

Discussion

Ischemic conditioning is well known as a novel strategy of protecting IR injury in coronary heart diseases, and is attracting extensive interest of clinical cardiologists. Cardiomyocytes acquire tolerability against IR injury not only by ischemic conditioning of itself, but also by ischemic conditioning of remote organs. Recent studies indicate that RIC treatment reduces the infarct size due to MI [23]. We focused on the possibility of therapeutic effect of RIC against CHF and demonstrated the

Funding sources

This study was supported in part by Grant-in-Aid for Scientific Research (24591101, 26460344 and 26461081) from the Ministry of Education, Culture, Sports, Science, and Technology, and Hoansha Foundation.

Conflicts of interest

The authors have no conflicts to report.

Acknowledgments

The authors would like to thank Ms. Chiori Asahi for her technical assistance.

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