New Cardiovascular and Pulmonary Therapeutic Strategies Based on the Angiotensin-Converting Enzyme 2/Angiotensin-(1–7)/Mas Receptor Axis

Ferreira, Anderson J.; Murça, Tatiane M.; Fraga-Silva, Rodrigo A.; Castro, Carlos Henrique; Raizada, Mohan K.; Santos, Robson A. S.

A growing body of studies has focused on the relevance of the ACE2/Ang-(1-7)/Mas axis in the pulmonary cancer pathophysiology. The protein expression of ACE2 is reduced in non-small-cell lung carcinoma (NSCLC) along with an increase in Ang II levels. Moreover, overexpression of ACE2 in cultured A549 lung cancer cells and in human lung cancer xenografs inhibited the cell growth and the vascular endothelial growth factor-a (VEGFa) expression induced by Ang II [123, 124] . Gallagher and Tallant [125] evaluated the effects of several angiotensin peptides [Ang I, Ang II, Ang-(2-8), Ang- (3) (4) (5) (6) (7) (8) , and Ang-(3-7)] in SK-LU-1 cancer cells growth, and only Ang-(1-7) showed significant attenuation of the DNA synthesis and proliferation. The antiproliferative effect of Ang-(1-7) was mediated by its receptor Mas and inhibition of the ERK1/2 pathway. Neither the blockage of AT 1 nor AT 2 succeeded in inhibiting the action of Ang-(1-7). In keeping with these data, the antiproliferative effect of Ang-(1-7) was observed in human A549 lung tumor xenograft growth along with a marked decrease in the vessel density in mice through a mechanism involving cyclooxygenase-2 (COX-2) [126, 127] . Of note, in a nonrandomized phase I clinical trial conducted by Petty and colleagues [38] , subcutaneous injections of Ang-(1-7) were administered in 18 patients with advanced solid tumors refractory to standard therapy. Despite the mild adverse effects observed with the Ang-(1-7) treatment, generally it was well tolerated. There were no treatment-related deaths. Clinical benefits were observed in 27% of the patients. Altogether, these studies provide insights into the involvement of the ACE2/Ang-(1-7)/Mas axis in lung cancer.