Angiotensin 1/2 (1-9) is a competitive inhibitor of Angiotensin-Converting Enzyme 2 (ACE2) that regulates cardiovascular remodeling[1]. Angiotensin 1/2 (1-9) inhibits cardiomyocyte hypertrophy via the Mas and Angiotensin type 2 receptor, and stimulates atrial natriuretic peptide (ANP) secretion via the AT2R-PI3K-Akt-NO-cGMP pathway[2]. Angiotensin 1/2 (1-9) has been widely used for the prevention and improvement of cardiovascular damage caused by activation of the renin-angiotensin system[3].
In vitro, Angiotensin 1/2 (1-9) treatment (1nM) for 48 hours resulted in a decrease in the number of cells in the G0/G1 phase and an increase in the number of cells in the S phase, and promoted cell migration in PNT1A cells[4]. Pretreatment with 1µM Angiotensin 1/2 (1-9) for 30 minutes inhibited fibroblast proliferation stimulated by serum[5]. 100µM of Angiotensin 1/2 (1-9) pre-incubation for 1 hour suppressed the apoptosis of human umbilical vein endothelial cells (HUVECs) induced by Ang II, increased cell viability and reduced the protein levels of Bax and cleaved-caspase-3[6].
In vivo, continuous administration of Angiotensin 1/2 (1-9) at a dose of 200ng/kg/min via a subcutaneously implanted osmotic minipump for 4 weeks alleviated myocardial hypertrophy, reduced myocardial fibrosis, and improved ventricular function in streptozotocin-induced diabetic rats[7]. Continuous administration of Angiotensin 1/2 (1-9) at a dose of 1200ng/kg/min via a subcutaneously implanted osmotic minipump for 14 days reduced blood pressure and alleviated vascular remodeling in spontaneously hypertensive rats[8].
References:[1] Ocaranza M P, Jalil J E. Protective role of the ACE2/Ang‐(1–9) axis in cardiovascular remodeling[J]. International journal of hypertension, 2012, 2012(1): 594361.
[2] Cha S A, Park B M, Gao S, et al. Stimulation of ANP by angiotensin-(1-9) via the angiotensin type 2 receptor[J]. Life sciences, 2013, 93(24): 934-940.
[3] Ocaranza M P, Michea L, Chiong M, et al. Recent insights and therapeutic perspectives of angiotensin-(1–9) in the cardiovascular system[J]. Clinical science, 2014, 127(9): 549-557.
[4] Domińska K, Kowalska K, Habrowska-Górczyńska D E, et al. The opposite effects of angiotensin 1-9 and angiotensin 3-7 in prostate epithelial cells[J]. Biochemical and biophysical research communications, 2019, 519(4): 868-873.
[5] Flores-Munoz M, Work L M, Douglas K, et al. Angiotensin-(1-9) attenuates cardiac fibrosis in the stroke-prone spontaneously hypertensive rat via the angiotensin type 2 receptor[J]. Hypertension, 2012, 59(2): 300-307.
[6] Guo C, Liu H, Li B, et al. Angiotensin-(1–9) prevents angiotensin II-induced endothelial apoptosis through CNPY2/PERK pathway[J]. Apoptosis, 2023, 28(3): 379-396.
[7] Zheng H, Pu S Y, Fan X F, et al. Treatment with angiotensin-(1-9) alleviates the cardiomyopathy in streptozotocin-induced diabetic rats[J]. Biochemical pharmacology, 2015, 95(1): 38-45.
[8] Norambuena-Soto I, Ocaranza M P, Cancino-Arenas N, et al. Angiotensin-(1–9) prevents vascular remodeling by decreasing vascular smooth muscle cell dedifferentiation through a FoxO1-dependent mechanism[J]. Biochemical pharmacology, 2020, 180: 114190.