Role of the Peroxisome Proliferator Activated Receptors in Hypertension

Abstract

Nuclear receptors represent a large family of ligand-activated transcription factors which sense the physiological environment and make long-term adaptations by mediating changes in gene expression. In this review, we will first discuss the fundamental mechanisms by which nuclear receptors mediate their transcriptional responses. We will focus on the PPAR (peroxisome proliferator-activated receptor) family of adopted orphan receptors paying special attention to PPARγ, the isoform with the most compelling evidence as an important regulator of arterial blood pressure. We will review genetic data showing that rare mutations in PPARγ cause severe hypertension and clinical trial data which show that PPARγ activators have beneficial effects on blood pressure. We will detail the tissue- and cell-specific molecular mechanisms by which PPARs in the brain, kidney, vasculature, and immune system modulate blood pressure and related phenotypes, such as endothelial function. Finally, we will discuss the role of placental PPARs in preeclampsia, a life threatening form of hypertension during pregnancy. We will close with a viewpoint on future research directions and implications for developing novel therapies.

Regulation of Epigenetic Modifications in the Placenta during Preeclampsia: PPARγ Influences H3K4me3 and H3K9ac in Extravillous Trophoblast Cells

“…It has already been shown in animal studies that the inhibition of PPARγ by antagonists, for example, T0070907, leads to reduced fetal growth [36]. In contrast, activation of PPARy appears to protect against IUGR induced through hypoxia in advanced pregnancy [63].…”

“…It has been shown that PPARγ stimulates trophoblast proliferation [33] and plays an important role in trophoblast invasion [34,35]. A lack of PPARγ leads to placental defects [36,37], an increase of proinflammatory cytokines [38] is associated with hypertension [36,39]. Placental PPARγ is produced by trophoblasts and endometrial stromal cells [30,40,41] and is known to be reduced in preeclampsia [32,42].…”

Salt-Sensitivity of Blood Pressure and Insulin Resistance

“…Compelling evidence suggest that PPARγ is also an important regulator of blood pressure. Various mutations in PPARγ, causing loss of function, have been shown to strongly associate not only with insulin resistance and diabetes but also with severe hypertension ( Barroso et al, 1999 ; Fang et al, 2021 ). In addition to these rare mutations, common variants of PPARγ may also play a role.…”

SUMOylation as a Therapeutic Target for Myocardial Infarction

“…Peroxisome Proliferator-Activated Receptor Isoforms-γ Peroxisome proliferator-activated receptors (PPARs) are ligandactivated transcription factors of the nuclear hormone receptor superfamily including three subtypes: PPAR-α, PPAR-β/δ, and PPAR-γ (90). Cellular energy expenditure is tightly controlled by the PPAR family of transcription factors exclusively in the nucleus (91).…”