Molecular Signals Elicited by GPCR Agonists in Hypertension, Cardiovascular Remodeling: Are MMPs and ADAMs Elusive Therapeutic Targets?

Abstract

Hypertension, the condition characterized by sustained elevated blood pressure, affects over 25% of adults in developed countries and is accompanied by pathological cardiac remodeling (i.e., hypertrophy and fibrosis), thus being a major risk factor for cardiac failure. Life style, the environment, genetic factors, diabetes or obesity can all promote development and progression of hypertension associated cardiovascular disease in part because these conditions induce an excess production of pro-hypertensive, pro-hypertrophic and pro-fibrotic agonists.Here we review signaling pathways shared by major agonists including angiotensin II, catecholamines and endothelins. At the cellular level, these agonists initiate disease signaling by activating cognate G protein-coupled receptors (GPCRs). Early events in agonist-signaling include Ca 2+ release from intracellular stores, Ca 2+ uptake from extracellular millieu into cells and reactive oxygen species (ROS) generation by NADPH oxidase. ROS production in turn contributes to activation of matrix metalloproteinases (MMPs) and 'a disintegrin and metalloproteinases' (ADAMs). Activated MMPs and ADAMs cleave growth factors, cytokines as well as cell surface receptors, including GPCRs. Excessive activation of MMPs and ADAMs links agonist receptors with transcription and translation of disease-associated genes, including those of MMPs and ADAMs. Recent research indicates a complex and dynamic regulation of MMPs and ADAMs activity and expression by agonists, which poses a significant challenge to strategies aiming at targeting specific MMPs or ADAMs in cardiovascular disease.

Melanopsin Variants as Intrinsic Optogenetic On and Off Switches for Transient versus Sustained Activation of G Protein Pathways

“…GPCR signals can be fast (ms to s) and transient, sustained and long-lasting (min to hr), or even constitutive, leading to different regulatory cellular mechanisms for adjusting physiological events such as synaptic plasticity [38] or activation of different protein kinases [39]. Changes in the temporal-and spatial-dependent regulation of these signals in particular involving G q -coupled signals can cause different diseases such as inflammatory [40] and cardiovascular [41] disease or addiction, dyskinesia, and obesity [42,43]. Thus, hOpn4L and mOpn4L now offer the opportunity to transiently or sustainably activate GPCR pathways to understand and control different temporally shaped G protein signals in health and disease.…”

Matrix Metalloproteinase-2 Mediates a Mechanism of Metabolic Cardioprotection Consisting of Negative Regulation of the Sterol Regulatory Element–Binding Protein-2/3-Hydroxy-3-Methylglutaryl-CoA Reductase Pathway in the Heart

“…Running Title: MMP-2/HMGCR cardioprotective pathway Xiang Wang (1,5) , Evan Berry (1,5) , Samuel Hernandez-Anzaldo (1,5) , Zamaneh Kassiri (2,3,4,5) and Carlos Fernandez-Patron (1,3,4,5) Xiang Wang, Evan Berry, and Samuel Hernandez-Anzaldo contributed equally.…”

General retrospective mega‐analysis framework for rare variant association tests

“…According to previous research, GPR62 is a protein‐encoding gene in humans, and GPR62 is related to pathways of the family of G protein–coupled receptors (GPCRs). Numerous research studies have identified associations between GPCRs and hypertensive disorders (Brinks & Eckhart, ; Harris, Cohn, Pesant, & Eckhart, ; Rockman, Koch, & Lefkowitz, ; X. Wang, Bosonea, Odenbach, & Fernandez‐Patron, ), with abnormal GPCR function leading to increased blood pressure (Yang, Villar, Armando, Jose, & Zeng, ).…”

“…Numerous research studies have identified associations between GPCRs and hypertensive disorders (Brinks & Eckhart, 2010;Harris, Cohn, Pesant, & Eckhart, 2008;Rockman, Koch, & Lefkowitz, 2002;X. Wang, Bosonea, Odenbach, & Fernandez-Patron, 2012), with abnormal GPCR function leading to increased blood pressure (Yang, Villar, Armando, Jose, & Zeng, 2016).…”