4 the remarkable property of ACE2 for potentially complex patients with isolated RVHF. Apelin/APJ is highly expressed in pulmonary vasculature [24]. Chandra et al. (2011) reported signiﬁcantly lower se- rum apelin levels in patients with PAH compared to control subjects [25]. Apelin expression also decreases in the pul- monary endothelial cells of the patients with PAH [26]. It was shown that PAH in mice may originate from the disruption of apelin signaling which is mediated by decreased activation of adenosine monophosphate-activated protein kinase and endothelial synthase (eNOS) [25]. Pyr-Apelin- 13 treatment has been reported to downregulate Ang II and endothelin-1 and could therefore attenuate RV hyper- trophy and diastolic dysfunction in rats with PAH [27]. Alastalo et al. (2011) have elegantly shown that apelin could have both autocrine and paracrine eﬀects against PAH in pulmonary vasculature [26]. Bone morphogenetic protein- mediated apelin autocrine production results in enhanced pulmonary arterial endothelial survival, proliferation, and migration which can protect the vasculature against PAH. Importantly, apelin autocrine function against PAH is based on attenuation of the pulmonary arterial smooth muscle cells response to growth factors and by promoting apoptosis [26]. 3. Role of ACE2 and Apelin in Diabetes (DM) and Diabetic Cardiovascular Complications Attenuation of Ang II-induced glomerular mesangial cell proliferation, oxidative stress, and collagen IV protein syn- thesis is thought to be the critical steps in ACE2-related protection of diabetic nephropathy [28, 29]. Even in non- diabetic mice loss of ACE2 contributes to increase in renal lipid peroxidation product formation and activation of MAPK and ERK 1/2 in glomeruli [30]. ACE2 mRNA has been shown to be reduced by more than half in both the glomeruli and proximal tubules of the diabetic patients compared to controls [31]. ACE2 treatment is believed to be critical in protection against diabetes induced nephropathy. rhACE2 treatment attenuated high glucose in cultured primary rat mesangial cells [32]. The potential role of Ang II in the induction of kidney injury in ACE2 knocked out mice has been reported [33]. In addition to the possibility of renal protective role of rhACE2 due to its antihypertensive eﬀect in diabetic subjects, rhACE2 also attenuates diabetic nephropathy via blockade of Ang II-induced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in mesangial cells [32]. Bindom et al. (2010) have elegantly shown that ACE2 gene therapy in mice results in reduced fasting blood glucose and glucose tolerance improvement in a diabetic mice model [34]. They also proved that ACE2 overexpression in diabetic mice signiﬁcantly reduces apoptosis which can be prevented by Ang 1–7 receptor blockade [34], further supporting the link between ACE2 and diabetic glycemic control [34, 35]. Several studies have shown an association between apelin levels and overt diabetes [36]. Erdem et al. (2008) demon- strated that plasma apelin was lower in newly diagnosed and untreated patients with DM II compared to healthy Cardiology Research and Practice controls [37]. Soriguer et al. (2009) showed the association between apelin levels and glucose concentrations and insulin sensitivity in diabetic patients suggesting the role of apelin in diabetes pathogenesis [38]. Furthermore, diabetic mice exhibited downregulation of apelin receptors and depressed aortic vascular tone [39]. However, Rittig et al. (2011) examined the association between apelin and atherosclerosis indicators (intima media thickness) in 344 subjects with an increased risk for DM II and did not show any association to diabetes risk pattern [40]. The eﬀect of apelin in DM control has been shown in some animal studies. Intracerebroventricular injection of apelin in mice leads to improved glucose homeostasis via NO-dependent pathway [41]. Injection of apelin-13 (400 pmol/kg) for 10 weeks considerably reduced the pan- creas endoplasmic reticulum (ER) stress in Akita mice, a model of DM I, which leads to modiﬁcation of pancreatic islet mass reduction and preservation of insulin content [42]. This important eﬀect of apelin-13 in type 1 diabetes was mediated by inhibition of inositol requiring enzyme 1-α and JNK pathways, suggesting apelin eﬀects on two important pathways of ER stress and cell death, respectively [42]. In mice with metabolic syndrome, apelin restores glucose toler- ance and increases glucose utilization [43]. Apelin treatment has a favorable eﬀect on vascular function in diabetic mice. Apelin treatment remarkably adjusts the abnormal aortic vascular reactivity in response to Ang II and acetylcholine in DM II mice by increasing the phosphorylation of Akt and eNOS [39]. Apelin may improve the glycemic status and insulin sensitivity of the patients and also can ameliorate vascular functions of diabetic patients. 4. Role of ACE2 and Apelin in Vascular Inﬂammation and Atherosclerosis The eﬀect of vascular inﬂammation in the initiation and pro- gression of atherosclerosis/cardiovascular diseases has been well recognized. Gene transfer of ACE2 suppresses the ex- pression of macrophage migration inhibitory factor, a proin- ﬂammatory cytokine associated with insulin resistance, in endothelial cells stimulated by Ang II [44]. ACE2 deﬁciency contributes to enhanced atherosclerotic plaque formation and also increases proinﬂammatory cytokines, including interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and vascular cell adhesion molecule-1, which deﬁned the key role of ACE2 in modulation of inﬂammation- dependent atherosclerosis development [44]. Remarkable eﬀects of rhACE2 on attenuation of Ang II-induced T- lymphocyte-mediated inﬂammation can be considered as an evidence for antiinﬂammatory/anti-atherosclerotic eﬀects of ACE2 [45]. ACE2 reduced atherosclerosis progression in apolipopro- tein E knockout mice probably by inhibition of reactive oxygen species (ROS) subsequent activities [46]. Association between ACE2 antiatherosclerotic eﬀects and disturbance of Ang II/Ang 1–7 peptides has been proved [47]. Zhang et al. (2010) suggested the downregulation of the ERK-p38, Janus kinase-signal transducer and activator of transcription