Cardiology Research and Practice system (JAK-STAT), and Ang II-induced ROS-nuclear factor kappa light chain enhancer of activated B cells (NF-kappaB) signaling pathways and upregulation of the phosphatidyli- nositol 3 kinases-protein kinase B (PI3K-Akt) pathway subsequent to ACE2 therapy in rabbits [48]. It has been shown that overexpression of ACE2 can readily stabilize the atherosclerotic plaques probably due to protective eﬀects of Ang 1–7 [49]. Hence we concluded that ACE2 is essential to prevent or delay the development of atherosclerosis. The plaque stabilizing eﬀect of ACE2 seems promising for prevention of acute coronary syndromes (ACS). Plasma levels of apelin inversely correlated to inﬂamma- tory markers (C-reactive protein and IL-6) in hemodialysis patients [50]. Apelin treatment in mice models of abdom- inal aorta aneurysm (AAA) clearly demonstrated its anti- inﬂammatory eﬀects that could attenuate AAA formation [51]. Injected apelin can reduce the mRNA levels of pro- inﬂammatory markers (MCP-1, macrophage inﬂammatory protein-1α, IL6 and tumor necrosis factor-α) [51]. Apelin attenuates ultraviolet B-induced edema and inﬂammation in mice and play an important role in stabilization of the tissue [52]. Apelin exerts acute anti-inﬂammatory eﬀects on the vascular system; the results are promising and if these results can be extrapolated in chronic models, it can be a proper therapeutic modality for prevention of inﬂammation in the process of atherosclerosis. Pitkin et al. (2010) have shown an increase in apelin expression in atherosclerotic coronary artery, with the additional peptide localizing to the atherosclerotic plaque [53]. Apelin receptor was also found to be present within the atherosclerotic plaque and to have a similar distribution to its ligand [53]. Increased content of apelin and its receptor might be an indicator of increased anti-inﬂammatory activation of macrophages thereby limiting plaque instability. Due to lack of data and contradictory ﬁndings, the exact role of apelin on atheroscle- rosis plaque remains inconclusive. 5. Role of ACE2 and Apelin in Angiogenesis The association between ACE2 and cardiac angiogenesis during the HF process has not been studied. A few studies in the cancer ﬁeld have supported an important role of ACE2 in angiogenesis [54, 55]. The probable adverse antiangiogic eﬀects of ACE2 in HF remain unclear. Apelin angiogenenic eﬀects have been proved in few animal studies; however none of the studies targeted the eﬀect of apelin on heart angiogen- esis. Tiani et al. (2009) showed the remarkable eﬀect of apelin on portosystemic collateralization and splanchnic neovas- cularization in portal hypertensive rats [56]. Treatment of human umbilical vein endothelial cells with apelin dose- dependently augments angiogenic responses [57]. Kidoya et al. (2010) indicated that apelin together with vascular endothelial growth factor (VEGF) eﬃciently induced func- tional vessels larger than with VEGF alone, in the hind limb ischemia model of mice [58]. Apelin is required factor for hypoxia-induced retinal angiogenesis in mice [59]. Available data imply that apelin is an eﬀective factor in angiogenesis; however none of the studies have targeted coronary vessels to 5 test the eﬀect of apelin on their angiogenesis. If the eﬀect of apelin on cardiac collateralization is proved in future studies, it can be considered as a valuable factor for the patients with HF, in particular ischemic HF. The probable oﬀ-or on-target eﬀects of apelin on other organs angiogenesis, for example, retinal neovascularization/angiogenesis make interpretation problematic. 6. Role of ACE2 and Apelin in Post-Myocardial Infarction (MI) Remodeling Post-MI remodeling and coronary artery disease are now the most common cause of HF [60]. In ACE2 deﬁcient mice, MI leads to enhanced activation of the RAS resulting in increased cardiac mortality, adverse ventricular remodeling, and aggravated systolic function [61]. ACE2 contributes to generation of myocardial Ang 1–7 after MI which may protect the heart from ischemic consequences [61]. Loss of ACE2 in post-MI mice is associated with increased Ang II levels and ROS production. This is followed by increased matrix metalloproteinase (MMP) activation, inﬂammation, and activation of MAPK in ACE2-deﬁcient hearts [61]. Der Sarkissian et al. (2008) analyzed the rats that received an intracardiac injection of lentivirus containing ACE2 cDNA followed by coronary artery ligation and found the ischemic protection of myocardium by ACE2 24 hours after the ischemic event compared to the control mice [62]. The eﬀect of ACE2 overexpression on attenuation of left ventricular ﬁbrosis/remodeling and systolic function was also shown one month after MI [63]. Ang II antagonist infusion for 28 days after MI results in augmented ACE2 cardiac mRNA in normotensive rats, which may be related to direct blockade of AT1R or the probable contribution of increased Ang 1–7 [64]. Attenuated cardiac hypertrophy and improved ventricular contractility both were chronic antiremodeling eﬀects of ACE2 on ACS- induced ischemia [64]. Treatment of the rats for a same period (28 days) with C16, a selective non-peptidic ACE2 inhibitor, at a dose that inhibited myocardial ACE2 activity was associated with a signiﬁcant increase in MI infarct size [65]. It seems that acute and long-term eﬀects of ACE2 limits the infract size following ACS. ACE2 is capable to produce Ang 1–9 from Ang I [4]. Ocaranza et al. (2010) proved the eﬃcacy of Ang 1–9 in attenuation of post-MI remodeling [66]. Further studies are needed to evaluate the eﬀect of ACE2 on Ang 1–9 increase and its remodeling-attenuation in coronary artery disease. Decreased levels of apelin-36 during 5 days interval following ST elevation MI have been reported [67, 68]. Weir et al. (2009) also conﬁrmed depressed level of apelin early after MI. They showed signiﬁcant increase of apelin from base line to 24 weeks after MI [69]. None of these studies found any relation between apelin levels and left ventricular function [67–69]. Kadoglou et al. (2010) showed that both groups of patients with unstable angina and acute MI had signiﬁcantly lower level of apelin compared to the patients with asymptomatic coronary artery disease [70]. According to our knowledge, only decreased levels of apelin after