Cardiology Research and Practice 3 Apelin Vasculature Endothelium Endothelium-dependent vasorelaxation: Modulates abnormal aortic vascular tone in NO release: cAMP accumulation inhibition (?) rpehsopsopnhsoertiolaAtinong II:↑Akt and eNOS ↓inﬂammation:↓hs-CRP,↓IL−6,↓TNFα ↓ER-stress: ↓CHOP,↓Caspase12,↓JNK Collateralization and neovascularization ↑pulmonary endothelial cell hemostasis: ↑BMP,↑eNOS,↑AMPK Diminish AAA formation: ↓aortic MCSF expression,↓MCP−1, ↓TNFα, ↓IL-6 ↓ROS:↓NADPH oxidase in vascular smooth muscle cells ↓pulmonary artery muscle cell proliferation Cardiomyocytes Protect I/R injury: ↑PI3K/Akt, AMPK and P44/42 phosphorilation; ↑ SOD activity, ↑ERK 1/2 ↓ROS, ↓CHOP, ↓Caspase 12, and ↓JNK Inotropic effect: activation of PLC, PKC, Na+/H+,and Na+ /Ca+2 exchangers Antagonize Ang II effects :PAI-1 inhibition, Rho kinase inhibition AF amelioration: propagation of action potential and contractility Vasodilation PAH Atherosclerosis Angiogenesis HTN PAH AAA Atherosclerosis I/R injury ↑Contractility Arrhythmia Remodeling Figure 2: Diverse eﬀects of apelin on cardiovascular system. Black arrows, eﬀects of apelin on various targets; Green arrows and red bars, favorable stimulatory and inhibitory eﬀects of apelin on cardiovascular system respectively; AAA: abdominal aorta aneurysm; AF: atrial ﬁbrillation; Akt: protein kinase B; AMPK: adenosine monophosphate-activated protein kinase; BMP: bone morphogenetic protein; CHOP: CCAAT/enhancer binding protein homologous protein; eNOS: endothelial synthase; hs-CRP: high sensitivity C-reactive protein; ER-stress: endoplasmic reticulum stress; ERK: extracellular signal-regulated kinase; HTN: hypertension; I/R: ischemia reperfusion; IL-6: interleukin 6; JNK: C-jun-N-terminal kinase; MCSF: macrophage colony stimulating factor; MCP-1: monocyte cheomattractant protein 1; NADPH: nicotinamide adenine dinucleotide phosphate; NO: nitric oxide; PAH: pulmonary arterial hypertension; PI3K: phosphatidylinositol 3- kinases; PKC:protein kinase C; PLC: Phospholipase-C; ROS: reactive oxygen species; SOD: superoxide dismutase; TNFα: tumor necrosis factor. expression and reduced proﬁlin-1 levels were associated with an overt suppression of ERK1/2 and JNK phosphorylation in aortas of spontaneously hypertensive rats [9]. ACE2 overexpression results in increased expression of various antihypertensive components of the RAS including Ang 1–7/Mas and AT2R. Vascular transgenic overexpression of ACE2 results in reduction of arterial blood pressure [10, 11] and an attenuated response to Ang II infusion [10]. Central nervous system overexpression of ACE2 also was proved to be protective against Ang II induced hypertension [12]. Wysocki et al. (2010) showed that acute Ang II infusion- induced hypertension can be prevented by rhACE2 pre- treatment (2 hrs before the Ang II infusion) in mice. This antihypertensive eﬀect of rhACE2 was associated with a decrease in plasma Ang II and increases in plasma Ang 1–7 levels. However, the antihypertensive eﬀect of rhACE2 was shown to be independent of Ang 1–7 in this study [13]. Wysocki et al. concluded that circulatory decrease of Ang II was the driving cause of decreased hypertension, rather than increased levels of Ang 1–7 [13]. This acute antihypertensive eﬀect of ACE2 seems promising for management of the patients with hypertension. Reduced circulating levels of apelin have been demon- strated in the patients with essential hypertension [14, 15]. Genetic variation in apelin likely contributes to essential hy- pertension and the onset of aged hypertension [16]. Tate- moto et al. (2001) showed that arterial pressure after the administration of apelin-12, apelin-13, and apelin-36 at a dose of 10 nmol/kg resulted in a reduction in arterial blood pressure [17]. Cheng et al. (2003) examined dose response curves of apelin (10, 20, and 40 nmol/kg) in rats and concluded that apelin is an arterial and venous dilator in vivo [18]. Japp et al. (2008) showed nitric oxide (NO)-dependent vasodilatory eﬀect of apelin in 24 healthy volunteers in vivo [19]. However, the long-term eﬀects of manipulating the apelin pathway and its eﬀect on blood pressure are unknown. Several studies focused on the role of ACE2 and apelin in amelioration of pulmonary arterial hypertension (PAH). Ang II is of fundamental importance to development and progression of PAH, due to its vasoconstrictive, ﬁbrotic, and proliferative eﬀects [20]. Left ventricular failure/remodeling is one of the frequent consequences of PAH which may aggravate the global function of the heart. The ability of ACE2 to combat the ﬁbrosis/proliferative eﬀects of Ang II on lung and right ventricle (RV) supported the beneﬁcial role of ACE2 in PAH treatment [20]. ACE2 overexpression [21] and ACE2 activation by 1-[(2-dimethylamino) ethylamino]- 4-(hydroxymethyl)-7-[(4-methylphenyl) sulfonyl oxy]-9H- xanthene-9-one (XNT) [22] ameliorate RV systolic failure, decrease the adverse eﬀects of Ang II, and attenuate pro- inﬂammatory cytokines in PAH mice. There is promising evidence of rhACE2 on improvement of RV load-stress (pulmonary artery banded (PAB)) of early HF [23]. rhACE2 administered to PAB mice for two weeks prevented load- induced RV systolic and diastolic dysfunction [23]. The exceptional increasing eﬀect of rhACE2 on RV [23] shows