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

Ana Zupcic; Nejla Latic; Mhaned Oubounyt; Alice Ramesova; Geert Carmeliet; Jan Baumbach; Maria L Elkjaer; Reinhold G Erben

doi:10.3390/ijms25115929

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Title (eng)

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

Author

Ana Zupcic

University of Veterinary Medicine Vienna

Nejla Latic

University of Veterinary Medicine Vienna

Mhaned Oubounyt

Alice Ramesova

University of Veterinary Medicine Vienna

Geert Carmeliet

Jan Baumbach

Maria L Elkjaer

Reinhold G Erben

University of Veterinary Medicine Vienna

Abstract (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.

Keywords (eng)

Vitamin DVitamin D ReceptorLeft Ventricular HypertrophyCardiomyocytesSpatial TranscriptomicsInflammationFibrosis

Type (eng)

journal article

Language

[eng]

Persistent identifier

https://phaidra.vetmeduni.ac.at/o:4446

DOI

10.3390/ijms25115929

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Title (eng)