The Angiotensin AT2 Receptor: From a Binding Site to a Novel Therapeutic Target.

Discovered more than 30 years ago, the angiotensin AT2 receptor (AT2R) has evolved from a binding site with unknown function to a firmly established major effector within the protective arm of the renin-angiotensin system (RAS) and a target for new drugs in development. The AT2R represents an endogenous protective mechanism that can be manipulated in the majority of preclinical models to alleviate lung, renal, cardiovascular, metabolic, cutaneous, and neural diseases as well as cancer. This article is a comprehensive review summarizing our current knowledge of the AT2R, from its discovery to its position within the RAS and its overall functions. This is followed by an in-depth look at the characteristics of the AT2R, including its structure, intracellular signaling, homo- and heterodimerization, and expression. AT2R-selective ligands, from endogenous peptides to synthetic peptides and nonpeptide molecules that are used as research tools, are discussed. Finally, we summarize the known physiological roles of the AT2R and its abundant protective effects in multiple experimental disease models and expound on AT2R ligands that are undergoing development for clinical use. The present review highlights the controversial aspects and gaps in our knowledge of this receptor and illuminates future perspectives for AT2R research. SIGNIFICANCE STATEMENT: The angiotensin AT2 receptor (AT2R) is now regarded as a fully functional and important component of the renin-angiotensin system, with the potential of exerting protective actions in a variety of diseases. This review provides an in-depth view of the AT2R, which has progressed from being an enigma to becoming a therapeutic target.

Controlling High Blood Pressure: An Evidence-Based Blueprint for Change.

Recently published national data demonstrate inadequate and worsening control of high blood pressure (HBP) in the United States, outcomes that likely have been made even worse by the coronavirus disease 2019 (COVID-19) pandemic. This major public health crisis exposes shortcomings of the US health care delivery system and creates an urgent opportunity to reduce mortality, major cardiovascular events, and costs for 115 million Americans. Ending this crisis will require a more coherent and systemic change to traditional patterns of care. The authors present an evidence-based Blueprint for Change for comprehensive health delivery system redesign based on current national clinical practice guidelines and quality measures. This innovative model includes a systems-based approach to ensuring proper BP measurement, assessment of cardiovascular risk, effective patient-centered team-based care, addressing social determinants of health, and shared decision-making. The authors also propose building on current national quality improvement initiatives designed to better control HBP.

Repressed Ang 1-7 in COVID-19 Is Inversely Associated with Inflammation and Coagulation.

The coronavirus SARS-CoV-2 infects host cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor, which belongs to an anti-inflammatory, anti-thrombotic counter-regulatory arm of the renin-angiotensin system (RAS). ACE2 dysfunction and RAS dysregulation has been explored as a driving force in acute respiratory distress syndrome (ARDS), but data from COVID-19 patients has been inconsistent and inconclusive. We sought to identify disruptions of the classical (ACE)/angiotensin (Ang) II/Ang II type-1 receptor (AT1R) and the counter-regulatory ACE2/Ang 1-7/Mas Receptor (MasR) pathways in patients with COVID-19 and correlate these with severity of infection and markers of inflammation and coagulation. Ang II and Ang 1-7 levels in plasma were measured by enzyme-linked immunosorbent assay (ELISA) for 230 patients, 166 of whom were SARS-CoV-2+. Ang 1-7 was repressed in COVID-19 patients compared to that in SARS-CoV-2 negative outpatient controls. Since the control cohort was less sick than the SARS-CoV-2+ group, this association between decreased Ang 1-7 and COVID-19 cannot be attributed to COVID-19 specifically as opposed to critical illness more generally. Multivariable logistic regression analyses demonstrated that every 10-pg/mL increase in plasma Ang 1-7 was associated with a 3% reduction in the odds of hospitalization (adjusted odds ratio [AOR] 0.97, confidence interval [CI] 0.95 to 0.99) and a 3% reduction in odds of requiring oxygen supplementation (AOR 0.97, CI 0.95 to 0.99) and/or ventilation (AOR 0.97, CI 0.94 to 0.99). Ang 1-7 was also inversely associated with pro-inflammatory cytokines and d-dimer in this patient cohort, suggesting that reduced activity in this protective counter-regulatory arm of the RAS contributes to the hyper-immune response and diffuse coagulation activation documented in COVID-19. IMPORTANCE Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a unique disease, COVID-19, which ranges in severity from asymptomatic to causing severe respiratory failure and death. Viral transmission throughout the world continues at a high rate despite the development and widespread use of effective vaccines. For those patients who contract COVID-19 and become severely ill, few therapeutic options have been shown to provide benefits and mortality rates are high. Additionally, the pathophysiology underlying COVID-19 disease presentation, progression, and severity is incompletely understood. The significance of our research is in confirming the role of renin-angiotensin system dysfunction in COVID-19 pathogenesis in a large cohort of patients with diverse disease severity and outcomes. Additionally, to our knowledge, this is the first study to pair angiotensin peptide levels with inflammatory and thrombotic markers. These data support the role of ongoing clinical trials examining renin-angiotensin system-targeted therapeutics for the treatment of COVID-19.