2 Cardiology Research and Practice Ang III Ang 1–9 ACE2 CPA APA ACE2 therapy Effects: Vasoconstriction Vascular inﬂammation Cell proliferation Fibrosis Hypertrophy Ang II A1TR ACE Chymase Activates: PKC, MAPK/ERK 1/2 JNK, JAK-STAT3, PI3K-Akt Increases: Proﬁlin, procollagen Fibronectin, TGF β1, IL-6, MCP-1, VCAM-1, T cell activity, MMIF, MMP, ROS, NADPH oxidase Angiotensinogen Renin Ang I (1–10) ACE2 PCP NEP PEP Effects: Vasodilation Endothelial protection Antiproliferative Antiﬁbrotic Antioxidative stress ACE ACE2 therapy Ang 1–5 Ang 1–7 Mas R Increases: NO release, eNOS activation, SOD, Catalase activity Decreases: Lipid peroxidation, NADPH oxidase activity, NF-κ B, TNFα, Cox-2, MAPK, ERK1/2 , CHOP, GRP-78 Atherosclerosis Hypertension Diabetic cardiovascular complications Remodeling/heart failure Atrial/ventricular arrhythmia Pulmonary arterial hypertension Figure 1: The enzymatic cascade involved in the renin-angiotensin system, key receptor systems, and the biological eﬀects mediated by Ang II and Ang 1–7. Solid black lines, enzymatic pathways; Broken lines, peptide agonist interacting with its key receptor; Green arrow, stimulatory eﬀects; Red arrow, pathologic eﬀects; Green bars; inhibitory eﬀects. ACE2: angiotensin-converting enzyme; Akt: protein kinase B; Ang: angiotensin; APA: aminopeptidase A; AT1R Ang II type 1 receptor; CHOP: CCAAT/enhancer binding protein homologous protein; Cox-2: cyclooxygenase-2; CPA: carboxypeptidase A; eNOS: endothelial synthase; ERK: extracellular signal-regulated kinase; GRP- 78: glucose regulated protein; IL-6: interleukin-6; JAK-STAT: Janus Kinase- signal transducer and activator of transcription system; JNK: C-jun-N-terminal kinase; MAPK: mitogen activated protein kinase; Mas R: Ang 1–7 receptor; MCP-1: monocyte cheomattractant protein 1; MMIF: macrophage migration inhibitory factor; MMP: matrix metalloproteinase; NADPH: nicotinamide adenine dinucleotide phosphate; NEP: neutral endopeptidase; NF-kappaB: nuclear factor kappa-light-chain-enhancer of activated B cells; NO: nitric oxide; PCP: prolyl carboxypeptidase (also known as angiotensinase C); PEP: prolyl endopeptidase; PI3K: phosphatidylinositol 3-kinases; PKC: protein kinase C; ROS: reactive oxygen species; SOD: superoxide dismutase; TGFβ1, transforming growth factorβ1; TNF α: tumor necrosis factor α; VCAM-1: vascular cell adhesion molecule-1. ACE2 (rhACE2) (2 mg/kg−1/d−1) reduces the Ang II-induced hypertension in mice, by reducing Ang II-mediated activa- tion of enhanced extracellular signal-regulated kinase 1/2 (ERK1/2), protein kinase C (PKC) pathways and renal ﬁbrosis [6]. It is suggested that ACE2 expression is decreased in the spontaneously hypertensive rats before the marked onset of hypertension [7]. It is believed that impaired renal level of ACE2 contributes to hypertension in humans [8]. Exposure of cultured human umbilical artery smooth muscle cells (HUASMCs) to Ang II results in a signiﬁcant increase in the mRNA and protein expression of proﬁlin-1, recently linked to cytoskeleton remodeling by activation of the hyper- trophic signaling through mitogen activated protein kinase (MAPK), ERK1/2 and C-jun-N-terminal kinase (JNK), in conjunction with reduced ACE2 activity [9]. Enhanced proﬁlin-1 expression and MAPK signaling in HUASMCs in response to Ang II was noticeably reduced by rhACE2 in an Ang 1–7-dependent manner [9]. Improvement of ACE2