Abstract
Insulin-like growth factor-1 (IGF-1) is an important regulator of cardiomyocyte homeostasis and cardiac structure, and the prosurvival and antiapoptotic effects of IGF-1 have been investigated. However, the effect of microRNA-320 (miR-320) in ischemia and reperfusion (I/R) by targeting IGF-1 is rarely discussed. We investigated the role of miR-320 in I/R injury. A total of 192 healthy female Wistar rats were divided into eight groups (n = 24). Rat heart I/R model was established. Hemodynamics, infarct size weight (ISW), heart function, and rat cardiomyocyte apoptosis were measured. Hypoxia-reoxygenation (H/R) in rat cardiomyocyte was used to simulate the I/R process. The mRNA levels of miR-320 and IGF-1, and proteins levels of IGF-1, IGF-1R, p-IGF-1R, p-ASK1, p-JNK, p-p38, Bcl-2, Bax and Caspase-3 were measured. In vivo inhibition of miR-320 expression significantly increased IGF-1 and IGF-1R mRNA levels, elevated the absolute values of SBP, DBP, MAP, ± dp/dtmax, LVEF and LVFS, decreased ISW, LVESD and LVEDd and the number of TUNEL positive cells, lowered the levels of p-ASK1, p-JNK, p-p38, Bax and Caspase-3 and increased expression of Bcl-2 compared to the I/R + NC group. Compared to H/R + NC group in vitro, miR-320 inhibition increased IGF-1 mRNA levels, inhibited cardiomyocyte apoptosis, down-regulated p-ASK, p-JNK, p-p38, Bax and Caspase-3 levels, and up-regulated Bcl-2 level. MiR-320 inhibition target elevated IGF-1 mRNA and protein levels, suppress early cardiomyocyte apoptosis of I/R, and inhibited ASK1-JNK/p38 pathway, which provides a new target for clinical study of I/R injury.
Highlights
Ischemia/reperfusion (I/R) occur in trauma, vascular reflow, thrombolysis treatment, percutaneous transluminal coronary angioplasty and organ transplantation [1]
In order to verify whether this 3′untranslated regions (UTR) region of Insulin-like growth factor-1 (IGF-1) is targeted by miR-320, wild-type (WT) and mutant reporters were constructed with GV126-IGF-1 3′-UTR
Co-transfection of miR-320 mimics and recombinant mutant GV126-IGF-1 3′-UTR, co-transfection of miR320 inhibitors and recombinant mutant GV126-IGF-1 3′UTR, and co-transfection of miR-320 negative control and recombinant vectors showed no luciferase activity. These results suggest that miR-320 binds to IGF-1 3′-UTR and inhibits IGF-1 expression
Summary
Ischemia/reperfusion (I/R) occur in trauma, vascular reflow, thrombolysis treatment, percutaneous transluminal coronary angioplasty and organ transplantation [1]. Rapid alterations in ion flux and renormalization of pH following reperfusion causes severe cytotoxicity and I/R injury characterized by cell death and functional deterioration as a result of restoration of blood flow [4, 5]. Such I/R injury causes local myocardial inflammation and apoptosis, resulting in irreversible damage to the myocardium [6]. Insulin-like growth factor-1 (IGF-1), acts as an essential regulator of cardiac structure, plays an important part in cardiomyocyte homeostasis, such as inhibition of apoptosis, inter alia promotion of cell growth, as well as augmentation of calcium signaling [12]. A previous study revealed that IGF-1 facilitated regeneration of infarcted myocardium and promoted survival of cardiac stem cells [13]
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