Molecular Signals Elicited by GPCR Agonists in Hypertension, Cardiovascular Remodeling: Are MMPs and ADAMs Elusive Therapeutic Targets?
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 Ca2+ release from intracellular stores, Ca2+ 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
Keywords: G protein-coupled receptors, hypertension, cardiovascular hypertrophy, cardiovascular fibrosis, signaling
pathways, metalloproteinases, β-myosin, hypertrophy.
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