Additionally, pharmacological and genetic (transgenic animals and gene transfer) approaches have evidenced the significance of ACE2 in cardiac pathologies. Despite some controversies concerning the consequences of the ACE2 deficiency, in general, evidences indicate a protective role of ACE2 in the heart [48, [52] [53] [54] [55] [56] [57] . Crackower and colleagues [52] were the first to demonstrate that genetic ablation of ACE2 results in severe blood-pressure-independent systolic impairment. Also, disruption of ACE2 was able to accelerate cardiac hypertrophy and shortened the transition period to heart failure in response to pressure overload by increasing local Ang II [54] . Recently, it has been demonstrated that loss of ACE2 enhances the susceptibility to myocardial infarction, with increased mortality, infarct expansion and adverse ventricular remodeling [56] . In keeping with these genetic findings, pharmacological inhibition of ACE2 exacerbated cardiac hypertrophy and fibrosis in Ren-2 hypertensive rats [58] . On the other hand, cardiac overexpression of ACE2 prevented hypertension-induced cardiac hypertrophy and fibrosis in spontaneously hypertensive rats (SHR) and in Ang-II-infused rats [59, 60] . Indeed, transfection of Lenti-ACE2 (lentivirus containing ACE2 cDNA) or Ad-ACE2 (recombinant adenovirus carrying the murine ACE2) into the surrounding area of the infarcted myocardium was protective against pathological remodeling and cardiac systolic dysfunction in a rat model of myocardial infarction [61, 62] . This effect was associated with decreased expression of ACE and Ang II and increased expression of Ang-(1-7) [62] . Collectively, these observations reveal that ACE2 effectively plays a protective role in the cardiac structure and function.