At present, cancers are becoming increasingly common in the clinic and are thus growing threats to human health. These diseases are major causes of human death. Doxorubicin (DOX), an anthracycline antibiotic, is one of the most commonly used broad-spectrum antitumor drugs and is highly effective. However, DOX has an inevitable toxic effect on the heart while killing cancer cells[1]. The cardiotoxicity caused by DOX severely limits its widespread application in clinical antitumor therapy[2]. How to reduce the toxicity of doxorubicin has become an urgent question to be answered. DOX easily accumulates in cardiomyocytes due to its high affinity for cardiomyocytes, causing cardiomyocyte injury[3]. It has been reported that DOX can lead to production of excessive reactive oxygen species, cause mitochondrial oxidative stress damage, induce cardiomyocyte apoptosis, and eventually lead to heart failure[4]. Therefore, inhibition of DOX-induced oxidative stress injury and cardiomyocyte apoptosis may be important therapeutic strategies for DOX-induced myocardial injury.
Peptides are bioactive substances with small molecular weights, simple structures and widespread tissue distributions[5]. They are intermediates between amino acids and proteins and have unique biological activity. Peptides are widely involved in biological events such as oxidative stress[6], cell proliferation[7] and apoptosis[8]. The numbers of studies on peptides in cardiovascular diseases are also increasing. For example, the calcitonin gene-related peptide α-CGRP exerts anti-hypertension effects, alleviates myocardial remodelling and promotes angiogenesis and myocardial survival[9]. The adiponectin agonist ADP355, an adiponectin-based active peptide, ameliorates DOX-induced cardiac injury by reducing oxidative stress and cardiomyocyte apoptosis[10]. The peptide osteocrin can reduce oxidative stress injury, inflammation, apoptosis and cardiac dysfunction in DOX-induced cardiac injury[11]. In addition, peptides have strong clinical significance for drug transformation because of their small molecular weights, low toxicity, good targeting ability and ability to easily enter cells[5]. Therefore, peptides may be novel tools for treating DOX-induced myocardial injury.
Phosphoinositide 3-kinase/Akt (PI3K/Akt) is a serine/threonine protein kinase that plays a vital role in regulating cardiomyocyte proliferation, apoptosis and glucose uptake[12, 13]. Akt has an important protective effect on cardiomyocytes under oxidative stress. A study has reported that DOX can significantly suppress the PI3K/Akt signalling pathway in cardiomyocytes, which is closely related to its cardiotoxicity[14]. Previous experiments have indicated that Shenmai Injection can sustain mitochondrial homeostasis and improve cardiac function by activating the AMPK and PI3K/Akt pathways in DOX-induced cardiotoxicity[15]. Therefore, targeting the PI3K/Akt signalling pathway has certain prospects for the treatment of DOX-induced myocardial injury.
In a previous study, we analysed the peptide profiles of heart tissue of normal mice and mice with DOX-induced cardiotoxicity and identified 236 differentially expressed peptides (fold change ≥ 2, P < 0.05)[16]. Among them, a 17-amino acid peptide from HSPB6, ASAPLPGFSAPGRLFDQ (HSP-17), with a Peptide Ranker score of 0.82 (http://bioware.ucd.ie/~compass/biowareweb/; a score greater than 0.5 indicates possible high bioactivity)[17], attracted our attention and was predicted to have cardioprotective effects. In this study, we used H9c2 cells to construct a stable DOX-induced cardiomyocyte injury model and proved that the HSP-17 peptide can increase cell viability, reduce the levels of LDH and ROS and reduce cardiomyocyte apoptosis. In addition, we also proved that HSP-17 can upregulate the expression of phosphorylated Akt (p-Akt) in a DOX-induced cardiomyocyte injury model and that LY294002 (LY)[18], a typical inhibitor of PI3K/Akt, can eliminate the protective effects of HSP-17. In summary, we innovatively elucidated the effects of the peptide HSP-17 in DOX-induced cardiomyocyte injury, providing a new idea for the treatment of DOX-induced myocardial injury.