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
Bibliographic record
Abstract
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.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".