The finding of the apelin APJ axis represents an

The finding of the apelin/APJ axis represents an impressive event in cardiovascular studies. As a result of various experimental and clinical studies conducted in vivo and in vitro, it has been indicated that apelin/APJ is a crucial mediator of cardiovascular homeostasis, which takes part in the pathogenesis of a number of major cardiovascular diseases, for example, ritanserin mg failure, atherosclerosis, hypertension, and atrial fibrillation. Nevertheless, disputes about the effect of apelin/APJ on atherosclerosis and hypertension are still continuing, and therefore, the role of the molecular pathway in the disease protection in humans should be examined more (Yu et al., 2014). The diverse status of hypertension, along with the action site of apelin, can lead to the difference in the levels of apelin change on the treatment drugs in question. However, the apelin/APJ system unquestionably represents a probable therapy target in the treatment of hypertension, and the laboratory findings of the present study have introduced a significant aspect of the apelin/APJ system as a therapeutic target in cardiovascular diseases (Lv et al., 2013a, Lv et al., 2013b; Xie et al., 2013). The relationship of apelin/APJ system with hypertension has been currently examined in a number of studies. Masked hypertension represents a meaningful indicator of cardiovascular diseases, and plasma apelin levels are observed to be considerably lower in the masked hypertensive group in comparison with normotensive controls (Papadopoulos et al., 2013). In patients having significant hypertension, circulating apelin levels are decreased as well and related in an independent way with more serious left ventricular systolic and diastolic function deterioration (Przewlocka-Kosmala et al., 2011). Furthermore, it is observed that hypertensive rats have decreased plasma apelin levels and down-regulation of APJ in kidneys (Najafipour et al., 2012). Malyszkoj et al. (Małyszko et al., 2006) reported that the apelin levels decreased in chronic renal disease. It was also stated that the apelin levels decreased in coronary artery patients receiving hemodialysis. It is estimated that apelin has a function in the physiopathology of possible cardiovascular diseases as well as chronic renal failure. In the light of this information, it is indicated that apelin can be used as a treatment approach for uremic cardiomyopathy in the future (Ladeiras-Lopes et al., 2008). It was observed that, in the kidneys, the highest level of APJ mRNA was in the inner strip of outer medulla, which represents an area in the kidney that undertakes a significant function in water and sodium balance. Furthermore, a direct tubular function of apelin has been demonstrated (Hus-Citharel et al., 2008). The endothelium and vasoactive substances originating from the endothelium play an important role in the local control of blood pressure. It was observed that the endothelial gene expression increased in the endothelial cells of some hypertensive patients and these findings support the possible role of the endothelium in the hypertension development (DeArtinano and Gonzalez, 1999; Kaplan, 1998; Kaplan, 1997; Kornitzer et al., 1999). As a consequence of the cardiovascular actions, which are observed for apelin, it is possible to imply that a future drug target for hypertension and heart failure treatment is presented by apelin (Kleinz and Davenport, 2005). The effects of apelin-APJ receptor on the regulation of blood pressure should be discussed. There are many studies indicating that the average blood pressure increases (Katugampola et al., 2001) and decreases after apelin application. It was interpreted that contradictory results in the literature might have originated from the fact that the researchers used different experimental animal models and from the differences in the types of apelin application. In spite of the contradictive results, the common finding of the researchers is the fact that the vascular effect of apelin is related to the endothelial integrity (Cheng et al., 2003; Salcedo et al., 2007; Tatemoto et al., 2001). Apelin causes endothelium-dependent vasodilatation by modulating NO or prostanoid release in the cases in which the endothelial integrity is preserved under in vivo conditions (Salcedo et al., 2007). However, if there is an endothelial dysfunction, apelin affects smooth muscle cells and causes the vasoconstrictive response (Katugampola et al., 2001). The effects of apelin on vascular tone may be due to the dynamic interaction between apelin-APJ system and angiotensinogen-AT-1. Studies performed on hypertensive rats showed that, all trans retinoic acid (aTRA) that regulates the G protein receptor signal decreases blood pressure and increases APJ-apelin expression. In hypertensive rats, apelin inhibits the renin angiotensin system, reducing blood pressure and cause decrease of APJ in the kidney and plasma apelin levels (Hus-Citharel et al., 2008, Nagano et al., 2013).