The Role of the ACE2/MasR Axis in Ischemic Stroke: New Insights for Therapy

Abstract

Ischemic stroke remains the leading cause of neurologically based morbidity and mortality. Current stroke treatment is limited to two classes of FDA-approved drugs: thrombolytic agents (tissue plasminogen activator (tPA)) and antithrombotic agents (aspirin and heparin), which have a narrow time-window (<4.5 h) for administration after onset of stroke symptoms. While thrombolytic agents restore perfusion, they carry serious risks for hemorrhage, and do not influence damage responses during reperfusion. Consequently, stroke therapies that can suppress deleterious effects of ischemic injury are desperately needed. Angiotensin converting enzyme-2 (ACE2) has been recently suggested to beneficially influence experimental stroke outcomes by converting the vasoconstrictor Ang II into the vasodilator Ang 1-7. In this review, we extensively discuss the protective functions of ACE2-Ang (1-7)-MasR axis of renin angiotensin system (RAS) in ischemic stroke.

Keywords: MasR; angiotensin converting enzyme-2; ischemic stroke; therapy.

Figure 1

Classification of stroke subtypes. Stroke is classified into two major forms—ischemic (85%) and hemorrhagic (15%) groups.

Figure 2

Classical and alternative pathways of the renin angiotensin system (RAS). In the classical axis of RAS, angiotensin-converting enzyme (ACE) converts angiotensin I (Ang I) into angiotensin II (Ang II). Ang II activates angiotensin type 1 receptor (AT1R) to trigger vasoconstriction, inflammation, fibrosis, and cellular hypertrophy, and apoptosis. In the alternative axis, ACE2 converts Ang II into Ang (1–7) or Ang I into Ang (1–9). Ang (1–9) is converted to Ang (1–7) by the enzymatic activity of ACE or neprilysin. Ang (1–7) binds to either AT2R or MasR to exert vasodilator, anti-inflammatory, and anti-apoptotic effects.

Figure 3

Pathophysiological mechanisms involved in ischemic stroke. The reduction in blood flow, nutrient supply, and energy as a result of cerebral artery occlusion leads to many complex pathophysiological events including energy failure, glutamate excitotoxicity, elevation of intracellular Ca²⁺ levels, peri-infarct depolarization (spreading depression), impairment of mitochondria function, generation of reactive oxygen species (ROS), activation of microglia, secretion of pro-inflammatory cytokines/chemokines, inflammatory responses, and cell death.