Abstract
Nearly 18 million people died from cardiovascular diseases in 2019, of these 85% were due to heart attack and stroke. The available therapies although efficacious, have narrow therapeutic window and long list of contraindications. Therefore, there is still an urgent need to find novel molecular targets that could protect the brain and heart against ischemia without evoking major side effects. Nuclear receptors are one of the promising targets for anti-ischemic drugs. Modulation of estrogen receptors (ERs) and peroxisome proliferator-activated receptors (PPARs) by their ligands is known to exert neuro-, and cardioprotective effects through anti-apoptotic, anti-inflammatory or anti-oxidant action. Recently, it has been shown that the expression of aryl hydrocarbon receptor (AhR) is strongly increased after brain or heart ischemia and evokes an activation of apoptosis or inflammation in injury site. We hypothesize that activation of ERs and PPARs and inhibition of AhR signaling pathways could be a promising strategy to protect the heart and the brain against ischemia. In this Review, we will discuss currently available knowledge on the mechanisms of action of ERs, PPARs and AhR in experimental models of stroke and myocardial infarction and future perspectives to use them as novel targets in cardiovascular diseases.
Highlights
Cardiovascular diseases (CVDs), with nearly 18 million estimated deaths globally represent the first cause of death worldwide, whereas stroke ranks second cause of death on this infamous list [1].Heart and brain are organs with low ability for regeneration and damage of these tissues is irreversible
peroxisome proliferator-activated receptors (PPARs)-α expression and activity are diminished in cardiac tissue of pressure overload–induced hypertrophy murine model [145], in hypertrophic heart of spontaneously hypertensive stroke-prone rats [146] and in hypoxic cardiomyocytes [147] leading to a reduction in the capacity for fatty acid oxidation and increased rates of glucose utilization
It has been shown that PPAR-γ and its coactivator PGC-1α is engaged in cell differentiation and mitochondria biogenesis as well as in neurodegeneration and neuroinflammation [190]
Summary
Cardiovascular diseases (CVDs), with nearly 18 million estimated deaths globally represent the first cause of death worldwide, whereas stroke ranks second cause of death on this infamous list [1]. Since already existing treatments against myocardial infarction and stroke have a very narrow therapeutic window and a long list of contraindications, there is still an urgent need to find a more effective and safer therapeutic strategies to protect myocardial and brain cells against hypoxia/ischemia. AhR has been reported to inhibit ERs activity through the binding to the inhibitory xenobiotic response element (iXRE) presented in ERs target genes, squelching of shared coactivators or increased proteasomal degradation of ERs [18]. In this Review, we will focus on the role of ERs, AhR and PPARs in cardio-, and neuroprotection during hypoxia/ischemia in preclinical studies
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