Insights into the Activity, Differential Expression, Mutual Regulation, and Functions of Matrix Metalloproteinases and A Disintegrin and Metalloproteinases in Hypertension and Cardiac Disease

Abstract

Hypertensive cardiac disease is a major cause of death worldwide. Causative factors of hypertension include environmental stressors, genetic predisposition, and common morbidities of lipid metabolism such as obesity and diabetes. These factors pathologically elevate the systemic production of vasoconstrictive G-protein-coupled receptor agonists. Pathological concentrations of these agonists upregulate the gene expression and proteolytic activity of matrix metalloproteinases (MMPs) and A disintegrin and metalloproteinases (ADAMs). Among the metalloproteinases that act in concert with other mediators to elevate the systemic blood pressure and to modulate the development of cardiovascular hypertrophy and fibrosis processes are MMP-2, MMP-7, ADAM-12, and ADAM-17. This review offers insights into the activity, differential expression, mutual regulation, and functions of these metalloproteinases. We further review evidence linking them to transcription factors, carrier proteins, and receptors for lipids. The emerging links between metalloproteinases and lipids are intriguing and suggest new therapeutic targets in hypertensive cardiac 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

“…Based on our hypothesis 13 that alterations in inflammatory or lipid metabolic genes may underlie the development of heart disease, which was being pursued by independent lines of research in our laboratory, we examined the cardiac expression of 56 genes comprising inflammatory and lipid metabolic transcription factors, enzymes, and mediators. The analysis revealed a large elevation of Srebf2 and Hmgcr (genes encoding SREBP-2 and HMGCR, respectively), as well as a decreased expression of Nr1h3 (which encodes a liver X receptor-α, a major lipid metabolic transcription factor) in Mmp2 −/− relative to WT mice ( Figure 2A).…”

Experimental and Clinical Findings Regarding Matrix Metalloproteinases in Cardiovascular Diseases

“…Berry et al [1] have reviewed insights into the activity, differential expression, regulation and functions of matrix metalloproteinases (MMPs) and A disintegrin and metalloproteinases. They also reviewed evidence linking them to transcription factors, carrier proteins, and receptors for lipids in hypertension and cardiac disease.…”

“…The authors [1] described the transcriptional regulation of MMPs by G-protein-coupled receptor agonists, proinflammatory mediators, growth factors and lipid mediators. In this context, it is worth pointing out that the intronic activation by nuclear factor (NF) of activated T cells c2 is critical to ischemia-induced MMP-2 in skeletal ischemic muscle [2] and that a novel intracellular MMP-2 isoform induced activation of a latent promoter in the first intron by oxidative stress and hypoxia [3].…”

“…Moreover, the participation of NF-κB in the activation of MMP-2 has been demonstrated in the aorta of 2-kidney, 1-clip (2K1C) rats [4] and in human umbilical vein endothelial cells submitted to shear stress [5]. MMP activation by chemical modification was also reviewed [1]. MMPs are regulated posttranslationally via proteolytic cleavage by other MMPs or oxidative stress [6,7,8].…”

“…Berry et al [1] also stated that measurements of MMP activity should be combined with mRNA and protein levels. It is worth pointing out that these levels may better represent MMP activity when TIMP levels are also evaluated.…”