Department of Biomedical Sciences, University of Veterinary Medicine, 1210 Vienna, Austria.
Institute for Computational Systems Biology, University of Hamburg, Albert-Einstein-Ring 8-10, 22761 Hamburg, Germany.
Int J Mol Sci. 2024 May 29;25(11):5929. doi: 10.3390/ijms25115929.
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, VDR 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, VDR, Mlcv2-Cre, and cardiomyocyte-specific VDR knockout (VDR) 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 VDR mice, while having comparable cardiomyocyte size and LV fibrosis to TAC VDR 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 VDR compared to VDR mice. Hence, our study supports the notion that vitamin D signaling in cardiomyocytes plays a protective role in the stressed heart.
维生素 D 缺乏与心血管疾病之间的关联仍然存在争议。本研究旨在进一步阐明维生素 D 信号在左心室（LV）肥厚和功能障碍发展中的作用。为了特异性敲除心肌细胞中的维生素 D 受体（VDR），将 VDR 小鼠与 Mlcv2-Cre 小鼠杂交。通过增加心脏后负荷来诱导 LV 肥厚，采用横主动脉缩窄（TAC）的方法。在 4 月龄雄性野生型、VDR、Mlcv2-Cre 和心肌细胞特异性 VDR 敲除（VDR）小鼠中进行假手术或 TAC 手术。正如预期的那样，TAC 诱导了明显的 LV 肥厚和功能障碍，通过超声心动图、主动脉和心导管术、心脏组织学和 LV 表达谱在手术后 4 周得到证实。假手术组小鼠在基因型之间没有差异。然而，与 TAC VDR 对照组相比，TAC VDR 小鼠虽然具有相似的心肌细胞大小和 LV 纤维化，但超声心动图测量的分数缩短和射血分数降低。心脏冷冻切片的空间转录组学显示，与 VDR 小鼠相比，TAC VDR 应激心脏组织龛中的促炎和促纤维化基因调控网络更为明显。因此，我们的研究支持这样一种观点，即心肌细胞中的维生素 D 信号在应激心脏中发挥保护作用。
