https://phaidra.vetmeduni.ac.at/o:4446 Ablation of Vitamin D Signaling in Cardiomyocytes Leads to Functional Impairment and Stimulation of Pro-Inflammatory and Pro-Fibrotic Gene Regulatory Networks in a Left Ventricular Hypertrophy Model in Mice Zupcic, Ana Ana Zupcic University of Veterinary Medicine Vienna Latic, Nejla Nejla Latic 0000-0001-5635-5175 University of Veterinary Medicine Vienna Oubounyt, Mhaned Mhaned Oubounyt Ramesova, Alice Alice Ramesova 0000-0001-7482-7818 University of Veterinary Medicine Vienna Carmeliet, Geert Geert Carmeliet Baumbach, Jan Jan Baumbach Elkjaer, Maria L Maria L Elkjaer Erben, Reinhold G Reinhold G Erben 0000-0003-0801-6958 University of Veterinary Medicine Vienna MDPI journal article open access eng The association between vitamin D deficiency and cardiovascular disease remains a controversial issue. This study aimed to further elucidate the role of vitamin D signaling in the development of left ventricular (LV) hypertrophy and dysfunction. To ablate the vitamin D receptor (VDR) specifically in cardiomyocytes, VDRfl/fl mice were crossed with Mlcv2-Cre mice. To induce LV hypertrophy experimentally by increasing cardiac afterload, transverse aortic constriction (TAC) was employed. Sham or TAC surgery was performed in 4-month-old, male, wild-type, VDRfl/fl, Mlcv2-Cre, and cardiomyocyte-specific VDR knockout (VDRCM-KO) mice. As expected, TAC induced profound LV hypertrophy and dysfunction, evidenced by echocardiography, aortic and cardiac catheterization, cardiac histology, and LV expression profiling 4 weeks post-surgery. Sham-operated mice showed no differences between genotypes. However, TAC VDRCM-KO mice, while having comparable cardiomyocyte size and LV fibrosis to TAC VDRfl/fl controls, exhibited reduced fractional shortening and ejection fraction as measured by echocardiography. Spatial transcriptomics of heart cryosections revealed more pronounced pro-inflammatory and pro-fibrotic gene regulatory networks in the stressed cardiac tissue niches of TAC VDRCM-KO compared to VDRfl/fl mice. Hence, our study supports the notion that vitamin D signaling in cardiomyocytes plays a protective role in the stressed heart. Vitamin D Vitamin D Receptor Left Ventricular Hypertrophy Cardiomyocytes Spatial Transcriptomics Inflammation Fibrosis http://creativecommons.org/licenses/by/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:4446/download 10.3390/ijms25115929 https://phaidra.vetmeduni.ac.at/o:605 application/pdf International Journal of Molecular Sciences issn:1422-0067 VoR International Journal of Molecular Sciences 25 11 3.22 MB 2024