Deletion of the Antioxidant Enzyme Methionine Sulfoxide Reductase‐A Impairs Autonomic Regulation and Exacerbates Angiotensin‐induced Hypertension and End‐Organ Damage

Abstract

Methionine sulfoxide reductase‐A (MsrA) reverses methionine oxidation. We hypothesized that MsrA protects against angiotensin II (AngII)‐induced autonomic and cardiovascular dysfunction. Blood pressure (BP) and heart rate (HR) were measured in MsrA−/− (n=13) and control C57BL/6 (n=7) mice by telemetry, before and during AngII infusion (1000 ng/kg/min). Baroreflex sensitivity (BRS, sequence technique), and cardiac vagal and sympathetic tone (HR responses to methylatropine and propranolol) were measured. In control mice, AngII increased mean BP and sympathetic tone while decreasing BRS and vagal tone (Table). The deleterious effects of AngII were exaggerated in MsrA−/− mice (Table). The antioxidant tempol (T, 1mM drinking water) completely reversed AngII‐induced hypertension and autonomic dysregulation in MsrA−/− mice (Table). Left ventricular (LV) dysfunction (decreased ejection fraction, increased volume/mass ratio), increased ascending aorta diameter, and aneurysms, assessed by echocardiography and post‐mortem histopathology, were present only in AngII‐infused MsrA−/− mice. In summary, MsrA deficiency impairs autonomic regulation and exacerbates AngII‐induced hypertension, LV dysfunction, and arterial pathologies. These results identify MsrA as a novel therapeutic target in hypertension. (HL14388, VA)