Abstract
<jats:p>The renin–angiotensin–aldosterone system (RAAS) is a key regulator of cardiovascular function, blood pressure, and overall systemic homeostasis. Over recent decades, extensive research has examined the role of genetic variations within the angiotensin-converting enzyme (ACE) gene in cardiovascular disease susceptibility and progression. Among these genetic variants, the ACE insertion/deletion (I/D) polymorphism is the most widely studied, resulting in three genotypes: II, ID, and DD. Numerous investigations have linked this polymorphism to several cardiovascular disorders, including severe coronary artery disease, in-stent restenosis, hypertension, and heart failure. Advances in the understanding of the RAAS have demonstrated that several intermediate peptides within this pathway possess important biological functions beyond their traditional role as metabolic intermediates. These peptides can be generated through alternative enzymatic pathways involving ACE2, a homolog of ACE. The discovery of ACE2 led to the characterization of the ACE2/angiotensin-(1–7)/Mas receptor axis, a counter-regulatory pathway that balances the classical RAAS. Within this system, angiotensin-(1–7) serves as the primary effector peptide and can be produced directly or indirectly from angiotensin I and angiotensin II through ACE2-dependent mechanisms. By activating the Mas receptor, angiotensin-(1–7) exerts protective cardiovascular, renal, and neurological effects, contributing to the maintenance of tissue homeostasis. Another important area of investigation involves the influence of ACE genotypes on responses to pharmacological RAAS inhibition. Evidence suggests that the efficacy of ACE inhibitors, angiotensin receptor blockers, and thiazide diuretics may differ according to genetic background. As precision medicine continues to evolve, a deeper understanding of ACE polymorphisms and RAAS biology may facilitate the development of personalized therapeutic strategies, ultimately improving cardiovascular disease prevention, risk stratification, and treatment outcomes.</jats:p>