Metalloproteinases in hypertension and cardiac disease: differential expression and mutual regulation

Abstract

Arterial hypertension, a condition characterized by sustained elevated blood pressure, is associated with pathological cardiac remodeling (i.e. cardiac hypertrophy and fibrosis) and is a major risk factor for cardiac failure. These processes can be triggered by excess vasoconstrictive agonists, which induce metalloproteinase-dependent shedding of growth factors to transactivate growth factor receptors and initiate disease signaling. Here, we review emerging evidence that agonist-activated metalloproteinases exhibit different expression patterns and mutual transcriptional regulation during the development of hypertension and cardiac remodeling.

Figure 1

Postulated signaling pathways involving metalloproteinases in agonist-induced hypertension and cardiac disease. Agonist activation of constitutively expressed metalloproteinases induces transcription of metalloproteinase genes as well as pro-hypertrophic and pro-fibrotic genes. This is a candidate model to explain the observed overexpression and mutual regulation among metalloproteinases, from the MMP and ADAM families, during the course of hypertension and remodeling. ECM: extracellular matrix; GqPCR: Gq protein-coupled receptor. PLC-β: phospholipase C isoform β. IP₃: inositol 1,4,5-triphosphate. DAG: 1,2-diacylglycerol. PKC: protein kinase C. ROS: reactive oxygen species. MMP: matrix metalloproteinase. ADAM: a disintegrin and metalloproteinase. Grb-2: growth factor receptor-bound protein 2. Sos: son of sevenless. MEK: mitogen-activated protein kinase kinase. ERK: extracellular signal-regulated kinases. PI3K: phosphatidylinositol 3-kinase. PIP₂: phosphatidylinositol (4,5)-bisphosphate. PIP₃: phosphatidylinositol (3,4,5)-bisphosphate. PDK-1: phosphoinositide-dependent protein kinase 1. TGF-β: transformation growth factor β. R-Smad: receptor-regulated Smad.