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Angiotensin (1-7)
Angiotensin (1-7)
Identifiers
Symbol	Angiotensin (1-7)
SCOP2	2PJ8 / SCOPe / SUPFAM

Angiotensin (1-7) (C
₄₁H
₆₂N
₁₂O
₁₁; Molecular weight = 899.02 g/mol; H-Asp-Arg-Val-Tyr-Ile-His-Pro-OH) is an active heptapeptide of the renin–angiotensin system (RAS). ^[1] It also known by the generic name talfirastide (development name TXA127).^[2]

In 1988, Santos et al demonstrated that angiotensin (1-7) was a main product of the incubation of angiotensin I with brain micropunch biopsies^[3] and Schiavone et al reported the first biological effect of this heptapeptide.^[4]

Benter et al were the first to report that Ang-(1-7) behaves in a way opposite to that of Ang II and that intavenous administration of Ang-(1-7) produces blood pressure lowering effects by activating its own receptor ^[5] Angiotensin (1-7) is a vasodilator agent affecting cardiovascular organs, such as heart, blood vessels and kidneys, with functions frequently opposed to those attributed to the major effector component of the RAS, angiotensin II (Ang II).^[6]

Synthesis

The polypeptide Ang I can be converted into Ang (1-7) by the actions of neprilysin (NEP)^[7] and thimet oligopeptidase (TOP)^[8] enzymes. Also, Ang II can be hydrolyzed into Ang (1-7) through the actions of angiotensin-converting enzyme 2 (ACE2). Ang (1-7) binds and activates the G-protein coupled receptor Mas receptor^[9] leading to opposite effects of those of Ang II.

Possible pathways

Action of neprilysin on angiotensin I or angiotensin II.
Action of prolyl endopeptidase on angiotensin I.
Action of ACE on angiotensin 1-9.
Action of neprilysin on angiotensin 1-9.
Action of ACE2 on angiotensin II.

Effects

Ang (1-7) has been shown to have anti-oxidant and anti-inflammatory effects.^[10]^[11] It helps protect cardiomyocytes of spontaneously hypertensive rats by increasing the expression of endothelial and neuronal nitric oxide synthase enzymes, augmenting production of nitric oxide.^[12]

Pharmacological interactions

Ang (1-7) contributes to the beneficial effects of ACE inhibitors and angiotensin II receptor type 1 antagonists.^[13]

Clinical trials

Talfirastide has been tested in people with COVID-19^[14] and stroke.^[15]

References

^ {I F Benter 1, D I Diz, C M Ferrario Cardiovascular actions of angiotensin(1-7) Peptides . 1993 Jul-Aug;14(4):679-84.}}
^ Wagener, Gebhard; Goldklang, Monica P.; et al. (28 July 2022). "A randomized, placebo-controlled, double-blinded pilot study of angiotensin 1–7 (TXA-127) for the treatment of severe COVID-19". Critical Care. 26 (1): 229. doi:10.1186/s13054-022-04096-9. ISSN 1364-8535. PMC 9332096. PMID 35902867.
^ Santos RA, Brosnihan KB, Chappell MC, Pesquero J, Chernicky CL, Greene LJ, and Ferrario CM (1988). "Converting enzyme activity and angiotensin metabolism in the dog brainstem". Hypertension. 11 (2): 125–37. doi:10.1161/01.hyp.11.2_pt_2.i153. PMC 280369. PMID 2831145.
^ Schiavone MT, Santos RA, Brosnihan KB, Khosla MC, Ferrario CM (1988). "Release of vasopressin from the rat hypothalamo-neurohypophysial system by angiotensin-(1-7) heptapeptide". PNAS. 85 (11): 4095–8. Bibcode:1988PNAS...85.4095S. doi:10.1073/pnas.85.11.4095. PMC 280369. PMID 3375255.
^ {I F Benter 1, D I Diz, C M Ferrario Cardiovascular actions of angiotensin(1-7) Peptides . 1993 Jul-Aug;14(4):679-84.}}
^ Santos RA, Sampaio WO, Alzamora AC, Motta-Santos D, Alenina N, Bader M, et al. (2018). "The ACE2/Angiotensin-(1-7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1-7)". Physiol Rev. 1 (98): 505–553. doi:10.1152/physrev.00023.2016. PMC 7203574. PMID 29351514.
^ Chappell MC (January 2016). "Biochemical evaluation of the renin-angiotensin system: the good, bad, and absolute?". American Journal of Physiology. Heart and Circulatory Physiology. 310 (2): H137-52. doi:10.1152/ajpheart.00618.2015. PMC 4796631. PMID 26475588.
^ Wilson BA, Nautiyal M, Gwathmey TM, Rose JC, Chappell MC (April 2016). "Evidence for a mitochondrial angiotensin-(1-7) system in the kidney". American Journal of Physiology. Renal Physiology. 310 (7): F637 – F645. doi:10.1152/ajprenal.00479.2015. PMC 4824145. PMID 26697984.
^ Santos RA, Simoes e Silva AC, Maric C, Silva DM, Machado RP, de Buhr I, Heringer-Walther S, Pinheiro SV, Lopes MT, Bader M, Mendes EP, Lemos VS, Campagnole-Santos MJ, Schultheiss HP, Speth R, Walther T (July 2003). "Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas". Proceedings of the National Academy of Sciences of the United States of America. 100 (14): 8258–63. Bibcode:2003PNAS..100.8258S. doi:10.1073/pnas.1432869100. PMC 166216. PMID 12829792.
^ Benter IF, Yousif MH, Dhaunsi GS, Kaur J, Chappell MC, Diz DI (2008). "Angiotensin-(1-7) prevents activation of NADPH oxidase and renal vascular dysfunction in diabetic hypertensive rats". American Journal of Nephrology. 28 (1): 25–33. doi:10.1159/000108758. PMID 17890855. S2CID 24219314.
^ El-Hashim AZ, Renno WM, Raghupathy R, Abduo HT, Akhtar S, Benter IF (July 2012). "Angiotensin-(1-7) inhibits allergic inflammation, via the MAS1 receptor, through suppression of ERK1/2- and NF-κB-dependent pathways". British Journal of Pharmacology. 166 (6): 1964–76. doi:10.1111/j.1476-5381.2012.01905.x. PMC 3402818. PMID 22339213.
^ Zisman LS, Meixell GE, Bristow MR, Canver CC (October 2003). "Angiotensin-(1-7) formation in the intact human heart: in vivo dependence on angiotensin II as substrate". Circulation. 108 (14): 1679–81. doi:10.1161/01.CIR.0000094733.61689.D4. PMID 14504185.
^ Benter IF, Yousif MH, Al-Saleh FM, Raghupathy R, Chappell MC, Diz DI (May 2011). "Angiotensin-(1-7) blockade attenuates captopril- or hydralazine-induced cardiovascular protection in spontaneously hypertensive rats treated with NG-nitro-L-arginine methyl ester". Journal of Cardiovascular Pharmacology. 57 (5): 559–67. doi:10.1097/FJC.0b013e31821324b6. PMC 3095755. PMID 21326110.
^ Self, Wesley H.; Shotwell, Matthew S.; et al. (11 April 2023). "Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor–Biased Ligand in Adults With COVID-19: Two Randomized Clinical Trials". JAMA. 329 (14): 1170–1182. doi:10.1001/jama.2023.3546. PMC 10091180. PMID 37039791. S2CID 258062415.
^ "Phase 2 Study of TXA127 in Post-ischemic Stroke Patients - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 7 December 2023.

[1] {I F Benter 1, D I Diz, C M Ferrario Cardiovascular actions of angiotensin(1-7) Peptides . 1993 Jul-Aug;14(4):679-84.}}

[2] Wagener, Gebhard; Goldklang, Monica P.; et al. (28 July 2022). "A randomized, placebo-controlled, double-blinded pilot study of angiotensin 1–7 (TXA-127) for the treatment of severe COVID-19". Critical Care. 26 (1): 229. doi:10.1186/s13054-022-04096-9. ISSN 1364-8535. PMC 9332096. PMID 35902867.

[3] Santos RA, Brosnihan KB, Chappell MC, Pesquero J, Chernicky CL, Greene LJ, and Ferrario CM (1988). "Converting enzyme activity and angiotensin metabolism in the dog brainstem". Hypertension. 11 (2): 125–37. doi:10.1161/01.hyp.11.2_pt_2.i153. PMC 280369. PMID 2831145.

[4] Schiavone MT, Santos RA, Brosnihan KB, Khosla MC, Ferrario CM (1988). "Release of vasopressin from the rat hypothalamo-neurohypophysial system by angiotensin-(1-7) heptapeptide". PNAS. 85 (11): 4095–8. Bibcode:1988PNAS...85.4095S. doi:10.1073/pnas.85.11.4095. PMC 280369. PMID 3375255.

[5] {I F Benter 1, D I Diz, C M Ferrario Cardiovascular actions of angiotensin(1-7) Peptides . 1993 Jul-Aug;14(4):679-84.}}

[6] Santos RA, Sampaio WO, Alzamora AC, Motta-Santos D, Alenina N, Bader M, et al. (2018). "The ACE2/Angiotensin-(1-7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1-7)". Physiol Rev. 1 (98): 505–553. doi:10.1152/physrev.00023.2016. PMC 7203574. PMID 29351514.

[pmid26475588-7] Chappell MC (January 2016). "Biochemical evaluation of the renin-angiotensin system: the good, bad, and absolute?". American Journal of Physiology. Heart and Circulatory Physiology. 310 (2): H137-52. doi:10.1152/ajpheart.00618.2015. PMC 4796631. PMID 26475588.

[pmid26697984-8] Wilson BA, Nautiyal M, Gwathmey TM, Rose JC, Chappell MC (April 2016). "Evidence for a mitochondrial angiotensin-(1-7) system in the kidney". American Journal of Physiology. Renal Physiology. 310 (7): F637 – F645. doi:10.1152/ajprenal.00479.2015. PMC 4824145. PMID 26697984.

[pmid12829792-9] Santos RA, Simoes e Silva AC, Maric C, Silva DM, Machado RP, de Buhr I, Heringer-Walther S, Pinheiro SV, Lopes MT, Bader M, Mendes EP, Lemos VS, Campagnole-Santos MJ, Schultheiss HP, Speth R, Walther T (July 2003). "Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas". Proceedings of the National Academy of Sciences of the United States of America. 100 (14): 8258–63. Bibcode:2003PNAS..100.8258S. doi:10.1073/pnas.1432869100. PMC 166216. PMID 12829792.

[pmid17890855-10] Benter IF, Yousif MH, Dhaunsi GS, Kaur J, Chappell MC, Diz DI (2008). "Angiotensin-(1-7) prevents activation of NADPH oxidase and renal vascular dysfunction in diabetic hypertensive rats". American Journal of Nephrology. 28 (1): 25–33. doi:10.1159/000108758. PMID 17890855. S2CID 24219314.

[pmid22339213-11] El-Hashim AZ, Renno WM, Raghupathy R, Abduo HT, Akhtar S, Benter IF (July 2012). "Angiotensin-(1-7) inhibits allergic inflammation, via the MAS1 receptor, through suppression of ERK1/2- and NF-κB-dependent pathways". British Journal of Pharmacology. 166 (6): 1964–76. doi:10.1111/j.1476-5381.2012.01905.x. PMC 3402818. PMID 22339213.

[pmid14504185-12] Zisman LS, Meixell GE, Bristow MR, Canver CC (October 2003). "Angiotensin-(1-7) formation in the intact human heart: in vivo dependence on angiotensin II as substrate". Circulation. 108 (14): 1679–81. doi:10.1161/01.CIR.0000094733.61689.D4. PMID 14504185.

[pmid21326110-13] Benter IF, Yousif MH, Al-Saleh FM, Raghupathy R, Chappell MC, Diz DI (May 2011). "Angiotensin-(1-7) blockade attenuates captopril- or hydralazine-induced cardiovascular protection in spontaneously hypertensive rats treated with NG-nitro-L-arginine methyl ester". Journal of Cardiovascular Pharmacology. 57 (5): 559–67. doi:10.1097/FJC.0b013e31821324b6. PMC 3095755. PMID 21326110.

[14] Self, Wesley H.; Shotwell, Matthew S.; et al. (11 April 2023). "Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor–Biased Ligand in Adults With COVID-19: Two Randomized Clinical Trials". JAMA. 329 (14): 1170–1182. doi:10.1001/jama.2023.3546. PMC 10091180. PMID 37039791. S2CID 258062415.

[15] "Phase 2 Study of TXA127 in Post-ischemic Stroke Patients - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 7 December 2023.

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PROFILPELAJAR.COM

Angiotensin (1-7)

Synthesis

Possible pathways

Effects

Pharmacological interactions

Clinical trials

References

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