Nuclear Receptors in Myocardial and Cerebral Ischemia—Mechanisms of Action and Therapeutic Strategies

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.

Host-microbiota interactions: The aryl hydrocarbon receptor in the acute and chronic phases of cerebral ischemia

“…The basic characteristics of AHR AHR is a ligand-controlled transcription factor (5), which is implicated in multiple physiological and pathological processes of many diseases, including inflammatory bowel disease (78), metabolic syndrome, and CNS diseases (79,80). Expression of AHR is widely detected in the CNS, such as in neurons, oligodendrocytes, monocytes/macrophages, astrocytes, microglia, and cerebral endothelial cells (81). AHR can regulate the expressions of target genes which relate to cell proliferation, metabolism and immune response (82).…”

Role of PPAR Receptor and Ligands in the Pathogenesis and Therapy of Hematologic Malignancies

“…By regulating renal organic transporters MATE-1 and OCT-2, PPAR deletion reduces cisplatin nephrotoxicity [29]. In mouse myeloid cells, knocking down PPAR γ in mouse myeloid cells led to cardiac hypertrophy and increased myocardial infarct size [30]. Studies in mice with macrophagespecific deletion of PPARγ have shown that PPARγ is required for the maturation of AAMacs [31].…”

Aspects of xenobiotics and their receptors in stroke

“…After experimental ischemia, there is already evidence that SERMs imitate the effect of estradiol, minimizing hormone‐dependent concerns. Tamoxifen substantially decreased infarct size and protected neurons from ischemia in rats treated to permanent MCAO (pMCAO) 85 . Recently, a novel type of estrogen receptor G protein‐coupled estrogen receptor (GPER, formerly known as GPR30) broadly distributed throughout the brain might possibly play a crucial role in estrogen‐mediated neuroprotective benefits in pathologies like stroke 86 .…”

“…Tamoxifen substantially decreased infarct size and protected neurons from ischemia in rats treated to permanent MCAO (pMCAO). 85 Recently, a novel type of estrogen receptor G protein-coupled estrogen receptor (GPER, formerly known as GPR30) broadly distributed throughout the brain might possibly play a crucial role in estrogen-mediated neuroprotective benefits in pathologies like stroke. 86 This study reported that the GPER can be taken as a potential therapeutic target for stroke, mainly in males, as they cannot be exposed to estrogen therapy.…”