It is well established that decreased brain blood flow, increased reactive oxygen species production (ROS), and pro-inflammatory mechanisms accelerate neurodegenerative disease progressions, including vascular cognitive impairment and dementia (VCID). Previous studies in our laboratory have shown that our novel glycosylated Angiotensin-(1-7) Mas receptor agonist PNA5 reverses cognitive deficits, decreases ROS production, and inhibits inflammatory cytokine production in our preclinical mouse model of VCID that is induced by chronic heart failure (CHF). Ischemic heart disease, typically caused by myocardial infarction (MI), is the leading cause of CHF. Clinical studies show that the most effective strategy to improve clinical outcomes for ischemic heart disease is early reperfusion of the ischemic tissue. This restoration of blood flow, however, potentiates a massive inflammatory response that results in cardiomyocyte death followed by local and global cardiac remodeling, called ischemia-reperfusion (IR) injury, which is also driven by reactive oxidative species (ROS), calcium overload, and inflammatory responses. Because our novel glycopeptide derivative of Angiotensin-(1-7), PNA5, has an improved half-life, decreases circulating inflammatory cytokines, and inhibits endothelial ROS production, we predicted that PNA5 will attenuate IR sequelae post-IR. Using a mouse model of IR and comprehensive functional, histological and morphological phenotyping, we demonstrate that administration of PNA5 improves heart outcomes post-IR and could potentially be a therapeutic for IR injury.