Alamandine
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Alamandine is a newly discovered member of renin-angiotensin system (RAS) with cardiovascular functions that are protective and opposing to the classical axis. Alamandine is a product of ACE2-dependent catalytic hydrolysis of Angiotensin A (Ang A) and can also be generated by decarboxylation of Aspartic acid residue of Ang-(1-7).[1] Ang A is Ala1-Ang II (alanine in place of aspartic acid). In mononuclear leucocytes Angiotensin II (Ang II) is converted to Ang A by decarboxylation of aspartic acid . Ang A is detected in human circulation and was shown to be higher in individuals with end-stage renal disease [1].
Receptor
Mice deficient of MrgD receptor showed myocardial pathology with dilated cardiomyopathy and a marked decrease in systolic function further supporting cardioprotective pharmacology of alamandine.
Vascular Actions
Alamandine produced endothelium-dependent vasorelaxation that was blocked by D-Pro7-Ang-(1-7), an MrgD receptor antagonist but not by A779, an antagonist of Mas receptor [2]. In agreement with this, Tetzner et al [3] showed that alamandine activated cAMP formation in endothelial and mesangial cells transfected with MrgD. Importantly, oral administration of 2-Hydroxy-prolyl β-cyclodextrin (HPβCD) Cyclodextrin-alamandine produced antihypertensive effect in spontaneously hypertensive rat (SHR) [2]. In the same model, vascular remodeling in the ascending aorta was also prevented that was associated with decreased pro-inflammatory (IL1β, TNF and CCL2) and pro-fibrotic factors (MMP2 and TGF β1), and increased pro-resolution markers (MRC1 and FIZZ1) [4].
Cardiac Actions
Almandine showed cardioprotective effects in experimental models of pressure overload. In mice undergoing transverse aortic constriction, Alamandine prevented cardiac hypertrophy and fibrosis that was shown to be mediated partly via decreased ERK1/2 phosphorylation, TGFβ1 and MMP2, and increased AMPKα phosphorylation [5].
Central Effects
Experimental evidence was provided for an important role of this peptide in the central regulation of blood pressure. A study by Marins et al [6] showed evidence for central regulation of hemodynamics specifically by acting on MrgD receptors in rostral insular cortex. Microinjection of alamandine in this area elevated mean arterial blood pressure and renal sympathetic activity that were blocked by D-Pro7-Ang-(1-7), an MrgD antagonist.
References
- ^ a b Jankowski, Vera; Vanholder, Raymond; van der Giet, Markus; Tölle, Markus; Karadogan, Sevil; Gobom, Johan; Furkert, Jens; Oksche, Alexander; Krause, Eberhard; Tran, Thi Nguyet Anh; Tepel, Martin; Schuchardt, Mirjam; Schlüter, Hartmut; Wiedon, Annette; Beyermann, Michael; Bader, Michael; Todiras, Mihail; Zidek, Walter; Jankowski, Joachim (February 2007). "Mass-spectrometric identification of a novel angiotensin peptide in human plasma". Arteriosclerosis, Thrombosis, and Vascular Biology. pp. 297–302. doi:10.1161/01.ATV.0000253889.09765.5f. Retrieved 28 May 2022.
- ^ a b Lautner, Roberto Queiroga; Villela, Daniel C.; Fraga-Silva, Rodrigo A.; Silva, Neiva; Verano-Braga, Thiago; Costa-Fraga, Fabiana; Jankowski, Joachim; Jankowski, Vera; Sousa, Frederico; Alzamora, Andreia; Soares, Everton; Barbosa, Claudiane; Kjeldsen, Frank; Oliveira, Aline; Braga, Janaina; Savergnini, Silvia; Maia, Gisele; Peluso, Antonio Bastos; Passos-Silva, Danielle; Ferreira, Anderson; Alves, Fabiana; Martins, Almir; Raizada, Mohan; Paula, Renata; Motta-Santos, Daisy; Klempin, Friederike; Kemplin, Friederike; Pimenta, Adriano; Alenina, Natalia; Sinisterra, Ruben; Bader, Michael; Campagnole-Santos, Maria Jose; Santos, Robson A. S. (12 April 2013). "Discovery and characterization of alamandine: a novel component of the renin-angiotensin system". Circulation Research. pp. 1104–1111. doi:10.1161/CIRCRESAHA.113.301077. Retrieved 28 May 2022.
- ^ Tetzner, Anja; Naughton, Maura; Gebolys, Kinga; Eichhorst, Jenny; Sala, Esther; Villacañas, Óscar; Walther, Thomas (15 August 2018). "Decarboxylation of Ang-(1-7) to Ala1-Ang-(1-7) leads to significant changes in pharmacodynamics". European Journal of Pharmacology. pp. 116–123. doi:10.1016/j.ejphar.2018.05.031. Retrieved 28 May 2022.
- ^ de Souza-Neto, Fernando Pedro; Silva, Mario de Morais E.; Santuchi, Melissa de Carvalho; de Alcântara-Leonídio, Thaís Cristina; Motta-Santos, Daisy; Oliveira, Aline Cristina; Melo, Marcos Barrouin; Canta, Giovanni Naves; de Souza, Leandro Eziquiel; Irigoyen, Maria Cláudia Costa; Campagnole-Santos, Maria José; Guatimosim, Silvia; Santos, Robson Augusto Souza; da Silva, Rafaela Fernandes (15 March 2019). "Alamandine attenuates arterial remodelling induced by transverse aortic constriction in mice". Clinical Science (London, England: 1979). pp. 629–643. doi:10.1042/CS20180547. Retrieved 28 May 2022.
- ^ Silva, Mário Morais; de Souza-Neto, Fernando Pedro; Jesus, Itamar Couto Guedes de; Gonçalves, Gleisy Kelly; Santuchi, Melissa de Carvalho; Sanches, Bruno de Lima; de Alcântara-Leonídio, Thaís Cristina; Melo, Marcos Barrouin; Vieira, Maria Aparecida Ribeiro; Guatimosim, Silvia; Santos, Robson Augusto Souza; da Silva, Rafaela Fernandes (1 January 2021). "Alamandine improves cardiac remodeling induced by transverse aortic constriction in mice". American Journal of Physiology. Heart and Circulatory Physiology. pp. H352–H363. doi:10.1152/ajpheart.00328.2020. Retrieved 28 May 2022.
- ^ Marins, Fernanda Ribeiro; Oliveira, Aline Cristina; Qadri, Fatimunnisa; Motta-Santos, Daisy; Alenina, Natalia; Bader, Michael; Fontes, Marco Antonio Peliky; Santos, Robson Augusto Souza (1 September 2021). "Alamandine but not Ang-(1-7) produces cardiovascular effects at the rostral insular cortex". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. pp. R513–R521. doi:10.1152/ajpregu.00308.2020. Retrieved 28 May 2022.