Endothelial-specific HDAC1 Mediates Aortic Stiffness, Cardiac Diastolic Dysfunction, and Kidney Damage in Male Diet-Induced Obese Mice

Diet-induced obesity (DIO) is a major risk factor for cardiovascular disease (CVD) and chronic kidney disease (CKD). Previous studies show that pan inhibition of histone deacetylase (HDAC) isoforms may alleviate obesity-related vascular, cardiac, or kidney dysfunction. HDAC1 is a key mediator of endothelial cell (EC) activation, and we previously showed that HDAC1 overexpression in EC reduces nitric oxide production and mediates endothelial dysfunction. However, it is unclear whether EC-specific HDAC1 drives CVD or CKD risk. We hypothesized that EC-specific HDAC1 mediates DIO-related aortic stiffness, cardiac dysfunction, and/or kidney damage. To test this hypothesis, we utilized male tamoxifen-inducible EC-specific HDAC1 (iEC-HDAC1) wildtype (WT) and knockout (KO) mice on a chronic high-fat diet (45% fat) for 20 weeks. On week 17, all mice were treated with tamoxifen for five consecutive days. Immunofluorescence confirmed the specificity of HDAC1 in EC of the iEC-HDAC1 KO and WT DIO mice. iEC-HDAC1 WT DIO male had similar body weight gain to iEC-HDAC1 KO DIO mice (WT (n=9): 12.20±1.74 g, KO (n=18): 11.06±1.37 g, unpaired T-Test, p=0.62). Pulse wave velocity (PWV, measure of aortic stiffness) and heart function were assessed with Vevo 3100 ultrasound technology. iEC-HDAC1 KO DIO mice had significantly reduced PWV compared to iEC-HDAC1 WT DIO mice (WT (n=8): 2.99±0.24 m/s, KO (n=7): 1.89±0.12 m/s; unpaired T-Test, p=0.002). Further, iEC-HDAC1 KO DIO mice had improved cardiac diastolic function compared to iEC-HDAC1 WT DIO mice (WT (n=5): 23.62±3.88 cm/s, KO (n=6): 14.73±3.18 cm/s, unpaired T-test, p=0.11). Ejection fraction and fractional shortening were not different (EF: unpaired T-test, n=5, p=0.92; FS: unpaired T-test, n=5, p=0.91). Kidney damage was assessed by histological staining with Masson’s trichrome blue to identify proximal tubular vacuoles and medullary interstitial fibrosis. An unbiased scorer was utilized to determine the vacuolar or fibrosis score, with 0 being no vacuoles or fibrosis and 2 being maximum vacuoles or fibrosis. We found that iEC-HDAC1 KO DIO mice had reduced proximal tubular vacuoles compared to iEC-HDAC1 WT DIO (WT (n=12): 0.98±0.08, KO (n=14): 0.55±0.12, unpaired T-test, p=0.0118). Also, iEC-HDAC1 KO DIO mice had reduced medullary interstitial fibrosis compared to iEC-HDAC1 WT DIO (WT (n=6): 0.67±0.14, KO (n=13): 0.37±0.05; unpaired T-test, p=0.0228). In summary, iEC-HDAC1 mediates aortic stiffness, cardiac diastolic dysfunction, and kidney damage in a chronic high-fat model of DIO. We conclude that HDAC1, specifically in EC, mediates obesity-related cardiovascular dysfunction and renal damage. NIH R25 DK 115353 - in partnership with: NIH U54 DK126087 UAB Childhood Cystic Kidney Disease Core Center (UAB-CCKDCC); NIH R01: 1R01DK134562-01A1 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.