Interplay between PI3K/AKT pathway and heart disorders

The PI3K/AKT signaling has crucial role in the regulation of numerous physiological functions through activation of downstream effectors and modulation of cell cycle transition, growth and proliferation. This pathway participates in the pathogenesis of several human disorders such as heart diseases through regulation of size and survival of cardiomyocytes, angiogenic processes as well as inflammatory responses. Moreover, PI3K/AKT pathway participates in the process of myocardial injury induced by a number of substances such as H2O2, Mercury, lipopolysaccharides, adriamycin, doxorubicin and epirubicin. In this review, we describe the contribution of this pathway in the pathoetiology of myocardial ischemia/reperfusion injury and myocardial infarction, heart failure, cardiac hypertrophy, cardiomyopathy and toxins-induced cardiac injury.


Introduction
The PI3K/AKT signaling has essential function in the regulation of numerous physiological processes through activation of downstream effectors which participate in the cell cycle transition and cell proliferation [1]. PI3K is lipid kinase that can phosphorylate the D3 hydroxyl group of the inositol ring of phosphoinositide lipids [2]. Based on their affinity for lipid substrates and their structure, PI3Ks can be classified into three main classes [3]. Different extracellular stimuli such as growth factors, cytokines and hormones can induce activity of PI3K. For instance, binding of EGF, PDGF and insulin-like growth factor [4,5] to the RTK region can induce autophosphorylation of certain tyrosine residues in the cytoplasmic section leading to activation of PI3K. Moreover, activity of PI3K can be induced by G-protein coupled receptors [6].
AKT has three isoforms with the first two ones having ubiquitous expression and high levels of expression in the brain, heart and lung [7]. Growth factors and G-protein coupled receptors can stimulate PtdIns [3,4] P2 and PtdIns [3][4][5] P3 to induce AKT recruitment to the plasma membrane, where it is phosphorylated at Thr308 and made active by PDK1 [8]. Subsequent phosphorylation of Ser473 residue is needed for full activity of AKT [9]. Following activation, AKT can phosphorylate a number of downstream targets, including GLUT, GSK-3, and mTOR [10]. PI3K/AKT pathway has imperative roles in the pathogenesis of several human disorders such as heart diseases through regulation of size and survival of cardiomyocytes, angiogenic processes as well as inflammatory responses [11]. In the current review, we describe the role of this pathway in the pathoetiology of myocardial ischemia/reperfusion (I/R) injury and myocardial infarction (MI), heart failure, cardiac hypertrophy, cardiomyopathy and toxins-induced cardiac injury. Cardiovascular disorders are constantly ranked as the foremost source of demise in the United States, surpassing all kinds of malignancies [12]. Coronary artery diseases have a prevalence of 7%. The incidence of heart failure ranges from 3.4 (per 1000 person years) for white women to 9.1 for black men [12].

Myocardial ischemia/reperfusion (I/R) injury, myocardial infarction (MI) and heart failure (HF)
Myocardial I/R injury has been shown to be induced by endoplasmic reticulum stress and consequent apoptotic processes. Experiments in a cellular model of hypoxia reoxygenation have shown up-regulation of the fatty acid binding protein FABP4 injured cells. siRNA-mediated silencing of this gene has led to enhancement of cell viability and reduction of LDH levels following hypoxia reoxygenation process. Moreover, FABP4 silencing has decreased rate of apoptosis and activity of caspase-3 following this challenge. FABP4 down-regulation could also inhibit endoplasmic reticulum stress through reduction of p-PERK, GRP78, and ATF6 levels and block the endoplasmic reticulum stress-associated apoptotic pathway. The latter has been reflected in reduction of pro-apoptotic molecules p-JNK, CHOP, Bax, and caspase-12, along with enhancement of expression levels of Bcl-2. Most notably, FABP4 silencing has led to activation of the PI3K/AKT signaling. Cumulatively, FABP4 silencing has a protective effect against hypoxia reoxygenation damage through suppression of apoptosis through increasing activity of the PI3K/AKT pathway [13] (Fig. 1).
Another experiment in an animal model of isoproterenolinduced myocardial ischemic injury has shown that administration of the traditional Chinese medicine chishao along with terpene glycoside can decrease serum concentrations of CK and LDH, improve energy metabolism and relieve myocardial injury. Notably, this therapeutic regimen could increase levels of p-AKT and p-mTOR, while decreasing caspase-3 and Bax/Bcl-2 levels. These effects have been abolished following exposure with a PI3K inhibitor, indicating that the cardioprotective effects of chishao-terpene glycoside are exerted through induction of activity of PI3K/ AKT/mTOR signaling [14].
Another combined in vitro and in vivo study has shown that urolithin A alleviates hypoxia/reoxygenation injury in myocardial cells and reduces size of MI and cell death in animals exposed to I/R. This agent could also enhance antioxidant aptitude of cardiomyocytes following mentioned challenge and reduce apoptosis of myocardial cells. Since these effects have been abrogated by a PI3K/AKT inhibitor, it has been revealed that urolithin A improves cardiac function following I/R injury probably via modulation of this pathway [15].
The cardioprotective triterpenoid Araloside C has been shown to suppress hypoxia-reoxygenation-induced apoptosis of cardiomyocytes, improve cell viability and attenuate the LDH leakage. Moreover, this agent could inhibit hypoxiareoxygenation-induced endoplasmic reticulum stress through reduction of PERK/eIF2α and ATF6 activities and downregulation of CHOP and caspase-12. These effects have been attributed to its impact on induction of HSP90 expression [16]. A mixed in vitro and in vivo study has shown that upregulation of BMI1 promotes cardiac fibrosis, deteriorate cardiac function and enhances proliferation and migratory potential of fibroblasts. On the other hand, BMI1 silencing has attenuated cardiac fibrosis and stopped cardiac dysfunction. Moreover, up-regulation of BMI1 has decreased expression of PTEN, increased expression of PI3K, and enhanced phosphorylation of Akt and mTOR ( Fig. 1). Notably, a PI3K/mTOR inhibitor could reverse the impact of BMI1 on cardiac fibroblasts. Taken together, BMI1 participates in the MI-associated cardiac fibrosis and dysfunction through influencing proliferation and migratory potential of cardiac fibroblasts at least partly via modulation of the PTEN/PI3K/AKT/mTOR pathway [17]. Table 1 shows the role of PI3K/AKT pathway in I/R injury, MI and HF.

Cardiac hypertrophy
Guan et al. have exposed male rats were to CIH and/or resveratrol to examine the cardioprotective effect of resveratrol and clarify the underlying mechanism. They have reported that CIH increases heart weight/body weight ratio and left ventricle weight/body weight ratio and induces left ventricular remodelling. Moreover, CIH has increased left ventricular posterior wall thickness, ejection fraction and fractional shortening, and increased apoptosis index and expression of oxidative markers. Notably, resveratrol could improve cardiac function and alleviate cardiac hypertrophy, oxidative stress, and apoptosis in CIH-treated rats. Mechanistically, resveratrol-induced activation of autophagy has been shown to be exerted through PI3K/AKT pathway-associated suppression of mTOR [60].
The traditional herbal medicine Qingda granule has also been demonstrated to protect against Ang II-induced cardiac hypertrophy through modulation of PI3K/AKT pathway. This agent could attenuate the Ang II-induce rise in blood pressure and decrease left ventricle ejection fraction and fractional shortening. Besides, Qingda granule could alleviate the increase in the heart weight/tibia length ratio, cardiac damage, hypertrophy, and apoptosis. In vitro investigations has verified the impact of Qingda granule in amelioration of the Ang-II-induced enhancement of cell surface area and quantities of apoptotic cells, increase in the expression of ANP and BNP, and activity of caspases-9 and -3. Notably, Qingda granule could partially amen accretion of ROS, mitochondrial membrane depolarization, cytochrome C release, over-expression of Bax, and reduction of p-PI3K, p-AKT, and Bcl-2 [61].
Another Chinese herbal medicine, namely Isorhamnetin has been found to guard against cardiac hypertrophy through modulation of this pathway [62]. Table 2 shows the role of PI3K/AKT Pathway in cardiac hypertrophy.

Diabetic cardiomyopathy
Carvacrol as a natural cymene-derived monoterpene has been found to reduce blood glucose levels and suppress diabetic-induced cardiac remodeling in animal models. These effects have been accompanied by down-regulation of Nppa and Myh7 mRNAs reduction of cardiac fibrosis. Notably, carvacrol can reestablish PI3K/AKT signaling, which was compromised in diabetic mice. This substance has enhanced phosphorylation of PI3K, PDK1, AKT, and AS160 and decreased phosphorylation of PTEN in these animals. Finally, Carvacrol has been shown to enhance   [59] membrane translocation of GLUT4. Cumulatively, the protective effect of Carvacrol against diabetic cardiomyopathy is exerted through reestablishing PI3K/AKT signaling-facilitated translocation of GLUT4 to the cell membrane [63]. Nicorandil has been shown to exert anti-apoptotic roles in diabetic cardiomyopathy. This drug could enhance serum level of NO and cardiac level of eNOS in the diabetic animals, amend cardiac dysfunction and decrease apoptosis rate. These effects have been blocked by administration of 5-HD, a substance that inhibits phosphorylation of PI3K, Akt, eNOS, and mTOR. Thus, the anti-apoptotic effect of nicorandil in diabetic cardiomyopathy is exerted through modulation of PI3K/Akt pathway [64]. Similarly, another experiment in a rat model of diabetic cardiomyopathy has shown that resveratrol amends heart dysfunction through suppression of apoptosis via the PI3K/AKT/FoxO3a pathway [65]. Table 3 shows the role of PI3K/AKT pathway in diabetic cardiomyopathy.

Other conditions
An in vitro study in H 2 O 2 -induced H9c2 cells has shown down-regulation of miR-129-5p. Moreover, this treatment has resulted in reduction of cell viability and induction of cell autophagy. Forced up-regulation of miR-129-5p could inhibit H 2 O 2 -induced cell injury. Besides, ATG14 has been fund tp be a target of miR-129-5p. miR-129-5p overexpression could also activate phosphorylation of PI3K/AKT/ mTOR pathway resulting in reduction of the autophagy    [79] and apoptosis in H 2 O 2 exposed cells. Taken together, miR-129-5p has a protecting role against H 2 O 2 -induced autophagy and apoptosis through decreasing levels of ATG14 via activating of PI3K/AKT/mTOR pathway [66].

Discussion
PI3K/AKT pathway is involved in the regulation of fundamental cellular processes, including migration of cells, translational response, and survival of cells. Thus, it can modulate cellular metabolism, vascular homeostasis and thrombogenic processes [80]. Accordingly, PI3K/AKT pathway has central roles in the regulation of function of cardiomyocytes and their size and survival. Moreover, this pathway can regulate activity of immune cells. Thus, it is not surprising that this pathway participate in the pathoetiology of myocardial I/R injury and MI, heart failure, cardiac hypertrophy, cardiomyopathy and toxins-induced cardiac injury. Most conducted researches in this field have assessed the impact of this pathway in the pathoetiology of myocardial I/R injury and MI revealing several targets for modulation of the effects of PI3K/AKT pathway.
Notably, PI3K/AKT pathway has an essential role in cardiac fibrosis. Alterations in the cardiomyocytes during the pathogenic processes in cardiac fibroblasts, abnormal proportion of collagen I/III, and the disproportionate synthesis and deposition of extracellular matrix are affected by this pathway. This process is a shared pathological alteration occurring in many cardiac disorders such as ischemic heart disease, hypertension, and heart failure. The role of PI3K/AKT signaling in these processes pathway is exerted through regulation of cell survival, apoptosis, growth and contraction of cardiac cells. Moreover, this pathway can also modulate expression of mTOR, GSK-3, FoxO1/3, and NOS in this process [81]. Preliminary results of in vitro and in vivo studies have shown dual inhibition of PI3K/Akt and mTOR pathways using BEZ235 can attenuate process of fibrosis [82]. Future studies are needed to assess the effect of different inhibitors of these pathways on cardiac fibrosis.
Moreover, PI3K/AKT has a fundamental role in the pathological processes leading to atherosclerosis initiating from formation of atherosclerotic plaques their rupture. The PI3Kγ isoform of PI3K which is over-expressed in the hematopoietic cells has a particular role in induction of inflammation during atherosclerosis [83]. A number of atherogenic stimuli such as IFNγ, TGFβ, and TNF-a can also activate PI3K/AKT signaling [83]. Development of atherosclerosis can also be affected by PI3K/AKT pathway through modulation of migration of vascular smooth muscle cells, adhesion of platelets, and expression of inflammatory molecules [84].
The cardioprotective effects of several traditional medicines have been shown to be exerted through modulation of activity of this signaling pathway. For instance, resveratrol, Qingda granule and Isorhamnetin have been shown to protect against cardiac hypertrophy through modulation of PI3K/AKT pathway. Urolithin-A, Celastrol, Nobiletin, Tacrolimu, Hesperidin, Elabela, Troxerutin, Kaempferide, Leonurine, Ginsenoside Rg1, Melatonin, Araloside-C and Anthocyanin are examples of substances that protect against MI-induced I/R injury or heart failure through modulation of PI3K/AKT pathway. A number of transcription factors and miRNAs such as miR-23a-5p, miR-221, miR-126, miR-129-5p, miR-1, miR-486-5p have also been found to be implicated in the pathogenesis of heart disease through modulation of this pathway. These effects have been verified through experiments in cellular and animal models of heart injury. However, clinical studies are lacking in this field.
Most notably, PI3K/AKT pathway is regulated by several non-coding genes including miRNAs, long non-coding genes and circular RNAs [85]. This finding represents the complexity of regulation of PI3K/AKT pathway and indicates that any targeted therapy against this pathway should consider the effects of these transcripts on the activity of this pathway to yield the highest effectiveness with the lowest side effects.

Conclusion
PI3K/AKT pathway represents a candidate for design of effective drugs for treatment of heart disorders and appropriate substances for prevention of these disorders. Based on the importance of PI3K/AKT pathway in the pathogenesis of heart diseases and abundance of therapeutic substances that modulate activity of this pathway, further researches in this field can facilitate discovery of novel modalities for treatment of heart disorders. Further studies are needed to find specific markers for identification of response of patients to PI3K/AKT-modulating agents used for treatment of heart disorders.