After myocardial injury or in response to chronically increased hemodynamic load, cardiac mass increases as a result of cardiomyocyte hypertrophy and ventricular wall thickening. Initially these changes are compensatory mechanisms which help to maintain ejection performance and heart function. With continued hemodynamic overload the heart becomes dilated and its walls thinner, resulting in a geometry that contributes to systolic dysfunction by increasing wall stress [110] . At the cellular level, cardiac myocytes increase in size (hypertrophy), rearrange within the myocardial matrix (cell slippage), and die, to be replaced by fibrous tissue, which include fibroblasts and collagen. These changes are collectively referred to as "remodeling" [111] . Cardiac remodeling has been consistently associated with an impaired prognosis in patients with hypertension, MI and chronic heart failure (CHF) [112] . Despite recent advances in our understanding of the ACE2/Ang-(1-7)/axis, the functional role of ACE2 in the heart is somewhat controversial. Crackower et al. [64] originally reported a progressive reduction in LV contractile function in ACE2-null mice without significant changes in fibrosis, left ventricular and cardiac myocyte hypertrophy, or in mean arterial pressure [64] . Interestingly, whereas plasma and tissue levels of Ang II were increased, a decrease in blood pressure was only observed in 6-month-old male ACE−/− homozygote mice but not in age-matched females or 3month-old males. Conversely, Gurley et al. [113] reported that ACE2 deletion enhanced the susceptibility to Ang IIinduced hypertension but had no effect on cardiac structure or function [113] . Huentelman et al. [114] showed that the ACE2 overexpression protects the heart from Ang II-induced hypertrophy and fibrosis. More recently, in SHR hypertensive rats Díez-Freire et al. by using lentiviral-based ACE2 gene transfer, attenuated cardiac fibrosis and hypertrophy [70] and also improved LV and remodeling after experimental MI [115] . Finally, Yamamoto et al. [116] reported that ACE2 deletion exacerbated pressure overload-induced cardiac dysfunction and remodeling that was associated with increased intracardiac Ang II levels and AT1R activation. The reasons for these discrepancies seem to be: (a) the genetic background of the mice used for ACE2 gene deletion [113] , (b) global versus tissue-specific ACE2 manipulation, or (c) the cardiac responses were monitored under basal or pathophysiological conditions.