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
Previously, we reported that cardiac matrix metalloproteinase (MMP)-2 is upregulated in hypertensive mice. How MMP-2 affects the development of cardiac disease is unclear. Here, we report that MMP-2 protects from hypertensive cardiac disease. In mice infused with angiotensin II, the lack of MMP-2 (Mmp2−/−) did not affect the severity of the hypertension but caused cardiac hypertrophy to develop earlier and to a greater extent versus wild-type (Mmp2+/+) mice, as measured by heart weight:body weight ratio and upregulation of hypertrophy and fibrosis markers. We further found numerous metabolic and inflammatory gene expression abnormalities in the left ventricle of Mmp2−/− mice. Interestingly, Mmp2−/− mice expressed greater amounts of sterol regulatory element–binding protein-2 and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (a target of sterol regulatory element–binding protein-2–mediated transcription and rate limiting enzyme in cholesterol and isoprenoids biosynthesis) in addition to markers of inflammation including chemokines of the C-C motif ligand family. We focused on the functionally related genes for sterol regulatory binding protein-2 and 3-hydroxy-3-methylglutaryl-coenzyme A reductase. The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, lovastatin, attenuated angiotensin II–induced cardiac hypertrophy and fibrosis in Mmp2−/− and wild-type (Mmp2+/+) mice, with Mmp2−/− mice showing resistance to cardioprotection by lovastatin. MMP-2 deficiency predisposes to cardiac dysfunction as well as metabolic and inflammatory gene expression dysregulation. This complex phenotype is, at least in part, because of the cardiac sterol regulatory element–binding protein-2/3-hydroxy-3-methylglutaryl-coenzyme A reductase pathway being upregulated in MMP-2 deficiency.
- hydroxymethylglutaryl-CoA reductase inhibitors
- matrix metalloproteinase 2
- sterol regulatory element binding proteins
- Received December 1, 2014.
- Revision received December 15, 2014.
- Accepted January 8, 2015.
- © 2015 American Heart Association, Inc.