Increasing evidence demonstrates that advanced glycation end products (AGEs) play a pivotal role in the development and progression of diabetic heart failure, although there are numerous other factors that mediate the disease response. AGEs are generated intra- and extracellularly as a result of chronic hyperglycemia. Then, following the interaction with receptors for advanced glycation end products (RAGEs), a series of events leading to vascular and myocardial damage are elicited and sustained, which include oxidative stress, increased inflammation, and enhanced extracellular matrix accumulation resulting in diastolic and systolic dysfunction. Whereas targeting glycemic control and treating additional risk factors, such as obesity, dyslipidemia, and hypertension, are mandatory to reduce chronic complications and prolong life expectancy in diabetic patients, drug therapy tailored to reducing the deleterious effects of the AGE-RAGE interactions is being actively investigated and showing signs of promise in treating diabetic cardiomyopathy and associated heart failure. This review shall discuss the formation of AGEs in diabetic heart tissue, potential targets of glycation in the myocardium, and underlying mechanisms that lead to diabetic cardiomyopathy and heart failure along with the use of AGE inhibitors and breakers in mitigating myocardial injury.

Angiotensin II represents a key molecule in hypertension and cerebrovascular pathology. By promoting inflammation and oxidative stress, enhanced Ang II levels accelerate the onset and progression of cell senescence. Sustained activation of RAS promotes end-stage organ injury associated with aging and results in cognitive impairment and dementia. The discovery of the angiotensin-converting enzyme ACE2-angiotensin (1–7)-Mas receptor axis that exerts vasodilator, antiproliferative, and antifibrotic actions opposed to those of the ACE-Ang II-AT1receptor axis has led to the hypothesis that a decrease in the expression or activity of angiotensin (1–7) renders the systems more susceptible to the pathological actions of Ang II. Given the successful demonstration of beneficial effects of increased expression of ACE2/formation of Ang1–7/Mas receptor binding and modulation of Mas expression in animal models in containing cerebrovascular pathology in hypertensive conditions and aging, one could reasonably hope for analogous effects regarding the prevention of cognitive decline by protecting against hypertension and cerebral microvascular damage. Upregulation of ACE2 and increased balance of Ang 1–7/Ang II, along with positive modulation of Ang II signaling through AT2receptors and Ang 1–7 signaling through Mas receptors, may be an appropriate strategy for improving cognitive function and treating dementia.

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