Role of the renin-angiotensin system in physiological and pathological cardiac hypertrophy - focus on the ACE2/Ang-(1–7)/Mas axis

Cardiac hypertrophy is a dynamic adaptive response of the heart to physiological and pathological stimuli. Physiological hypertrophy, such as that induced by exercise training and pregnancy, is generally associated with preserved cardiac function and reversible remodeling. In contrast, pathological hypertrophy is characterized by fibrosis, oxidative stress, inflammation, and progression to heart failure. Among the major regulatory systems involved in cardiac remodeling, the renin–angiotensin system (RAS) plays a central role in both adaptive and maladaptive cardiac growth. While activation of the classical ACE/Ang II/AT1 receptor axis promotes pathological remodeling, the counter-regulatory ACE2/Ang-(1–7)/Mas axis exerts important cardioprotective effects by attenuating pathological cardiac hypertrophy and fibrosis. In addition, growing evidence indicates that this protective axis also contributes to the appropriate development of physiological hypertrophy, particularly during exercise training and pregnancy, supporting adaptive cardiac growth and remodeling. In this review, we provide an overview of the RAS and the general characteristics of physiological and pathological cardiac hypertrophy, highlighting the role of the ACE2/Ang-(1–7)/Mas axis as a key regulator of cardiomyocyte growth, myocardial remodeling, and cardiac adaptation under physiological and pathological conditions.