Recombinant Human ACE2 and the Angiotensin 1-7 Axis as Potential New Therapies for Heart Failure

Abstract

Heart failure (HF) is a common cause of death and disability and a major economic burden in industrialized nations. Heart disease remains the leading cause of death in North America, with ischemic and hypertensive heart disease as the leading cause of HF. Various basic and clinical studies have established the role of an activated renin-angiotensin (Ang) system and Ang II generation in the progression of HF. Inhibition of an activated renin-Ang system using Ang-converting enzyme inhibitors, Ang II type 1 receptor blockers, and mineralocorticoid receptors antagonists have shown clinical benefits in patients with HF, although, largely limited to HF with reduced ejection fraction (HF-rEF). In contrast, there is no approved pharmacotherapy for HF with preserved ejection fraction (HF-pEF). Ang-converting enzyme (ACE) 2 (ACE2) is a homolog of ACE, which, being a monocarboxypeptidase converts Ang II into Ang 1-7 and is downregulated in HF. Various preclinical studies have shown a potent cardioprotective role of ACE2/Ang 1-7 axis in HF, which counter-regulates the ACE/Ang II/Ang II type 1 receptor axis. Importantly, ACE2 and Ang 1-7 show substantial benefit in preclinical models of HF-pEF and HF-rEF. Improvement in endothelial dysfunction, suppression of tissue inflammation and myocardial fibrosis, correction of metabolic dysfunction, and reversal of pathological hypertrophy are the key beneficial effects seen when ACE2 or Ang 1-7 action are enhanced. Clinical benefit of recombinant human ACE2 and Ang 1-7 need to be evaluated in patients with HF-rEF and HF-pEF.