Myocardial Ischemia Reperfusion Injury Is Alleviated by Curcumin
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Liao et al. Stem Cell Research & Therapy (2021) 12:89 https://doi.org/10.1186/s13287-020-02101-y RESEARCH Open Access Myocardial ischemia reperfusion injury is alleviated by curcumin-peptide hydrogel via upregulating autophagy and protecting mitochondrial function Chi-Lin Liao1†, Yang Liu2†, Meng-Zhao Huang1, Hua-Yong Liu1, Zi-Liang Ye3 and Qiang Su3* Abstract Background: Ischemia-reperfusion injury (IRI) is an important factor limiting the success of cardiac reperfusion therapy. Curcumin has a significant cardioprotective effect against IRI, can inhibit ventricular remodeling induced by pressure load or MI, and improve cardiac function. However, the poor water solubility and low bioavailability of curcumin restrict its clinical application. Methods: In this study, we prepared and evaluated a curcumin-hydrogel (cur-hydrogel) to reduce cardiomyocyte apoptosis and reactive oxygen species formation induced by hypoxia-reoxygenation injury, promote autophagy, and reduce mitochondrial damage by maintaining the phosphorylation of Cx43. Results: Meanwhile, cur-hydrogel can restore cardiac function, inhibit myocardial collagen deposition and apoptosis, and activate JAK2/STAT3 pathway to alleviate myocardial ischemia-reperfusion injury in rats. Conclusions: The purpose of this study is to elucidate the protective effects of cur-hydrogel on myocardial ischemia-reperfusion injury by regulating apoptosis, autophagy, and mitochondrial injury in vitro and in vivo, which lays a new theoretical and experimental foundation for the prevention and reduction of IRI. Keywords: Ischemia-reperfusion injury, Autophagy, Apoptosis, Curcumin, Hydrogel Background ischemia-reperfusion injury is not completely clear. At The reperfusion therapy of acute myocardial infarction present, the mechanisms with more evidence include can lead to more serious dysfunction after myocardial is- oxidative stress, intracellular calcium overload, vascular chemia, resulting in the decrease of myocardial diastolic endothelial injury, endoplasmic reticulum stress, and in- and systolic function, the decrease of ventricular thresh- flammatory response [3, 4]. To develop effective drugs old, and the shortening of refractory period, which can or treatments to reduce myocardial ischemia-reperfusion be manifested as malignant arrhythmia, cardiac insuffi- injury has become a key problem to be solved urgently. ciency, and even sudden death [1, 2]. The mechanism of Curcumin is a polyphenolic compound extracted from the rhizome of curcuma. As an effective ingredient of * Correspondence: [email protected] traditional Chinese medicine turmeric, curcumin has a †Chi-Lin Liao and Yang Liu contributed equally to this study as co-first variety of pharmacological effects, such as anti- author. inflammation, anti-oxidation, anti-apoptosis, anti- 3Department of Cardiology, Affiliated Hospital of Guilin Medical University, No. 15, Lequn Road, Xiufeng District, Guilin 541001, Guangxi Zhuang fibrosis, anti-tumor, cardiovascular protection, and so Autonomous Region, People’s Republic of China on. Studies have shown that curcumin has a protective Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Liao et al. Stem Cell Research & Therapy (2021) 12:89 Page 2 of 11 effect on myocardial ischemia-reperfusion injury and can by pentobarbital sodium according to their body weight. reduce oxidative stress injury and cardiomyocyte apoptosis The ECG were monitored and recorded by [5]. Curcumin can also inhibit angiotensin II-mediated electrocardiograph. myocardial fibrosis [6] and cardiac non-benign ventricular Cut the skin of the rat neck with aseptic scissors, fully remodeling caused by left ventricular pressure overload [7] expose the trachea, intubate the trachea with an indwell- by regulating the expression of angiotensin receptor. It can ing needle, connect the small animal ventilator, give arti- also reduce myocardial hypertrophy caused by diabetic car- ficial ventilation (pressure 3kpa, frequency 70 times/ diomyopathy and improve cardiac function [8]. Curcumin min) to assist breathing, open the chest in the left fifth can also improve the cardiac function of rats after myocar- auxiliary room beside the sternum, separate the pericar- dial infarction in a dose-dependent manner [9] and can dium, fully expose the heart, the left coronary artery is prevent the progression of heart failure after myocardial in- located between the left atrial appendage and the pul- farction [10]. In the treatment of heart failure, curcumin monary artery, and use a small curved needle at 1–2mm can inhibit myocardial fibrosis and inhibit the activation of under the left atrial appendage. The left anterior de- myocardial fibroblasts by regulating TGF-β/Smads signal- scending branch of the coronary artery was ligatured at ing pathway to reduce collagen synthesis and reduce ven- the upper 1/3 of the left anterior descending branch tricular remodeling after heart failure [11]. However, (note that the needle depth was not more than 1 mm, curcumin has poor water solubility, easy oxidation in vitro, and the width was not more than 3 mm). The color of and low bioavailability. For example, in the human pharma- the anterior wall of the distal end of the coronary artery cokinetic test, volunteers takealargedoseofcurcumin12g was observed to become purplish red. ECG monitoring per day, but the blood concentration is too low to be de- showed that the ST segment in lead I, II, avL of ECG el- tected, and its metabolic degradation is very fast. These evated 0.2 mV as a sign of successful operation. 40 μM, shortcomings seriously restrict the wide clinical application 20 μL curcumin or cur-hydrogel was injected to ven- of curcumin [12, 13]. tricular wall at the bilateral 1 mm of the ligation site In order to increase the water solubility and bioavail- with an insulin injection needle (30 G), and then, the ability of curcumin, various dosage forms of curcumin chest was closed and sutured. AG490 (3 mg/kg) was carriers have been developed, such as polymer nanopar- injected intraperitoneally 30 min before operation in the ticles, polymer micelles, microemulsions, microspheres, model of heart injury. This study has been approved by liposomes, and polymer hydrogels [14]. These carriers the Animal Experimental Ethics Committee of Affiliated greatly improve the water solubility and bioavailability of Hospital of Guilin Medical University and was carried curcumin by encapsulation, chemical bond linking, or out in accordance with the National Institutes of Health physical adsorption. The degradation products of small guide for the care and use of Laboratory animals (NIH molecular hydrogels of polypeptides are amino acids, Publications No. 8023, revised 1978). The rats were which have the advantages of easy degradation, high bio- raised in the SPF animal room of the Clinical Research compatibility, non-toxicity, and safety, and have been Center of the Affiliated Hospital of Guilin Medical Uni- widely used in biological fields such as three- versity, feeding standard chow diet with light-dark cycle dimensional cell culture, drug controlled release, biosen- for 12 h. After the termination of experiments, the rats sor, and so on. At present, cur-hydrogels are mainly were euthanized by an anesthetic overdose. made of high molecular hydrogels (such as galactose, chitosan, gelatin, chitin, and polyacrylamide gelatin) or Cardiac hemodynamic measurement covalently linked to cur-hydrogels [15]. It has been stud- A small latex balloon filled with water was inserted into ied that polypeptide Nap-GFFYG-RGD and curcumin the left atrium by polyethylene intubation and entered monomer were assembled into small molecular polypep- into the left ventricle. The pressure transducer was con- tide hydrogel, which significantly improved the anti- nected to measure the left ventricular diastolic pressure tumor effect [16]. (LVDP), left ventricular end-diastolic pressure (LVEDP), In this study, we prepared a kind of hydrogel as curcu- and the maximum rate of rise and fall of left ventricular min carrier in order to improve the bioavailability of pressure. The data were input into the computer to curcumin. We hypothesize that cur-hydrogel may have a analyze and record them. better therapeutic effect on heart ischemia-reperfusion injury and explore its mechanism. Cardiac ultrasound examination of cardiac function Five mice in each group were randomly selected for car- Methods diac ultrasound 4 weeks