br Roles of apelin and APJ in cardiovascular diseases br

Roles of apelin and APJ in cardiovascular diseases
Therapeutic potential of apelin/APJ in cardiovascular diseases Since the apelin/APJ system plays a key role in the occurrence and development of cardiovascular diseases, it seems logical to presume that targeting this axis should be feasible and represent a new class of potential therapeutic agents. In agreement, exogenous administration of apelin significantly reduces LV end-diastolic volume and end-systolic volume as well as elevates LVEF in dogs with advanced heart failure [91]. High-dose of atorvastatin has been shown to attenuate early carotid atherosclerosis in patients with type 2 diabetes by upregulation of apelin expression [92]. Treatment with embryonic stem cells induces recruitment of vascular PCs in infarcted hearts, thereby improving repair postmyocardial infarction [50], [93]. Given the short circulating half-life of apelin peptide, apelin analogs or modification must be developed to avoid this limitation. Recently, Iturrioz et al. synthesized the first non-peptidic agonist of apelin receptor APJ, namely E339-3D6, which shows a 90nM affinity and serves as a partial agonist for cAMP production and a full agonist for APJ internalization [94]. This compound can induce the vasorelaxation of rat MCB-613 precontracted with norepinephrine, and potently suppress systemic vasopressin release in water-deprived mice when intracerebroventricularly injected [94]. Wang et al. also designed two novel apelin analogs resistant to angiotensin converting enzyme 2 cleavage and identified one analog, which mimicked the function of apelin [95]. They found that the apelin analog is protective against ex vivo and in vivo MIRI resulting from greater activation of survival pathways and promotion of angiogenesis [95]. Also, structural analogs of apelin-12 can limit myocardial infarction [96]. In addition, Jia and colleagues have successfully produced a 40kDa polyethylene glycol (PEG) conjugated apelin-36 (PEG-apelin-36), which is characterized by N-terminal conjugation, high purity (>98%), minimum reduction of APJ binding affinity and a prolonged circulating life [97]. Similar increases in cardiac EF are observed during the infusion of PEG-apelin-36 and apelin-36 in normal rats, whereas animals that received PEG-apelin-36 maintain significantly increased EF over the 100min post infusion monitoring period compared with apelin-36-treated animals; EF increases observed with PEG-apelin-36 and apelin-36 are greater in the myocardial infarction rats [97]. However, the roles of APJ agonism and apelin PEGylation need to be assessed in vivo in human. Of note, apelin has the ability to enhance gastric acid secretion as well [98], and may represent an important side effect that could have implications for its tolerability in cardiovascular disease patients.
Conclusion and future directions The discovery of the apelin/APJ axis is an exciting affair in cardiovascular research. Experimental and clinical investigations performed both in vivo and in vitro have suggested apelin/APJ as a critical mediator of cardiovascular homeostasis involved in the pathogenesis of several main cardiovascular diseases including atherosclerosis, CHD, heart failure, hypertension, PAH, MIRI and atrial fibrillation. However, the impact of apelin/APJ on atherosclerosis and hypertension is still controversial, and thus the contribution of the molecular pathway to disease protection in humans remains to be further explored. Although some synthetic agonists of APJ have therapeutic potential for reducing the risk of cardiovascular diseases [94], [95], [96], the safety and long term effect of these agonists needs to be more fully characterized and better defined. In addition to these, there are still many problems left to be solved. How are apelin and APJ regulated in vivo? Are there any other components required for their function? Are there efficient approaches to enhance their cardiovascular physiological actions besides APJ agonists? What is the exact diagnostic and prognostic role of apelin/APJ in cardiovascular disease patients? In answering these and many other questions, we will assuredly strengthen our chances of developing apelin/APJ-based therapies to help further decrease cardiovascular disease risk in future generations.