In MI Ocaranza et al. [51] observed that (a) circulating and LV enzymatic activities of ACE2 were downregulated in the long-term phase of LV dysfunction in rats, (b) these effects were prevented by the conventional ACE inhibitor enalapril, (c) plasma Ang-(1-9) levels were significantly increased when MI rats or sham-operated rats were treated with enalapril for 8 weeks but circulating Ang-(1-7) levels did not change at that time ( Figure 1) Ang-(1-9) Figure 3 : Signaling events and cellular effects induced by Ang II via AT1R and opposing effects of Ang-(1-9) acting through AT2R. Proposed Ang-(1-9)-dependent mechanisms that antagonize the cardiovascular remodeling effects of Ang II. ACE2 can directly cleave Ang I to form Ang- (1) (2) (3) (4) (5) (6) (7) (8) (9) . This peptide activates the AT2R to initiate signaling pathways that antagonize AT1R-mediated tyrosine kinase cascades. In this simplified scenario, Ang-(1-9) increases SHP-1 tyrosine phosphatase activity to inactivate src-dependent signaling. AT2R activation also acts other pathways such as NO-AKT. AT1R: Ang II type 1 receptor; AT2R: Ang II type 2 receptor; ERK1/2: extracellular signal-regulated kinase 1/2; JAK: Janus-activated kinase; MAPK: mitogen-activated protein kinase; p38: p38 MAPK; PKC: protein kinase C; STAT: signal transducer and activator of transcription; NO: nitric oxide; SHP-1: protein tyrosine phosphatase SH2 domain-containing phosphatase 1; MEK: mitogen/ERK kinase. Solid arrows indicates activation broken arrows indicates inactivation. findings, it was proposed in this model of HF, that Ang-(1-9) rather than Ang-(1-7) acts as a counterregulator of Ang II [51] .