PPARγ deacetylation prevents matrix metalloproteinase 2 dysregulation in postmenopausal mice

Background: Matrix metalloproteinase (MMP) activities significantly increase during menopause and post-menopause. It is well-established that MMP-2 dysregulation is linked to osteoporosis, metabolic disturbances, and vascular remodeling. Peroxisome proliferator-activated receptor gamma (PPARγ), a master regulator of metabolism and vascular function, can be regulated by de(acetylation). Our lab has demonstrated that PPARγ deacetylation possesses a protective vascular-metabolic effect. Based on our findings in PPARγ deacetylation and that PPARγ acts as a negative regulator of MMPs, we hypothesize that PPARγ deacetylation protects against MMP-2 dysregulation in post-menopause. Methods: Three-month-old C57BL/6 (WT) and 2KR female mice were randomized into control groups undergoing Sham surgeries (WT-SHAM, n=6; 2KR-SHAM, n=6) and ovariectomy groups (WT-OVX, n=6; 2KR-OVX, n=6), which involved bilateral ovary removal. After 24 weeks post-OVX, serum from all experimental groups was obtained for MMP analysis. MMP-2 expression and activity were assessed using gelatin zymography and western blotting. Statistical analyses were performed using GraphPad Prism 10 with two-way ANOVA for group comparisons. Results: As expected, postmenopausal induction in WT mice significantly increased MMP-2 activity (18.5±0.4 U vs. 1.4±0.3 U WT SHAM) and expression (2.5±0.06 U vs. 2.0±0.2 U WT SHAM). Strikingly, 2KR menopausal mice did not display changes in MMP-2 activity (2.0±0.8 U vs. 5.5±0.6 U 2KR SHAM) and expression (2.8±0.2 U vs. 2.6±0.1 U 2KR SHAM), conferring a protective role of PPARγ deacetylation in post-menopause. Conclusion: This is the first study showing a cross-talking between PPARγ deacetylation and MMP-2. PPARγ deacetylationrepresents a potential therapeutic target in treating MMP-2-related disorders found in post-menopause. NIH-NHLBI This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.