Calcification is common in chronic vascular disease, yet its role in pulmonary hypertension due to left heart disease is unknown. Here, we probed for the role of runt-related transcription factor-2 (RUNX2), a master transcription factor in osteogenesis, and its regulation by the HIPPO pathway transcriptional coactivator with PDZ-binding motif (TAZ) in the osteogenic reprogramming of pulmonary artery smooth muscle cells and vascular calcification in patients with pulmonary hypertension due to left heart disease. We similarly examined its role using an established rat model of pulmonary hypertension due to left heart disease induced by supracoronary aortic banding.

Pulmonary artery samples were collected from patients and rats with pulmonary hypertension due to left heart disease. Genome-wide RNA sequencing was performed, and pulmonary artery calcification assessed. Osteogenic signalling via TAZ and RUNX2 was delineated by protein biochemistry. In vivo, the therapeutic potential of RUNX2 or TAZ inhibition by CADD522 or verteporfin was tested in the rat model.

Gene ontology term analysis identified significant enrichment in ossification and osteoblast differentiation genes, including RUNX2, in pulmonary arteries of patients and lungs of rats with pulmonary hypertension due to left heart disease. Pulmonary artery calcification was evident in both patients and rats. Both TAZ and RUNX2 were upregulated and activated in pulmonary artery smooth muscle cells of patients and rats. Co-immunoprecipitation revealed a direct interaction of RUNX2 with TAZ in pulmonary artery smooth muscle cells. TAZ inhibition or knockdown decreased RUNX2 abundance due to accelerated RUNX2 protein degradation rather than reduced de novo synthesis. Inhibition of either TAZ or RUNX2 attenuated pulmonary artery calcification, distal lung vascular remodelling and pulmonary hypertension development in the rat model.

Pulmonary hypertension due to left heart disease is associated with pulmonary artery calcification that is driven by TAZ-dependent stabilisation of RUNX2, causing osteogenic reprogramming of pulmonary artery smooth muscle cells. The TAZ–RUNX2 axis may present a therapeutic target in pulmonary hypertension due to left heart disease.

钙化在慢性血管疾病中很常见，但其在左心疾病引起的肺动脉高压中的作用尚不清楚。在这里，我们探讨了主转录因子 runt 相关转录因子 2 （RUNX2） 在成骨中的作用，以及其在 HIPPO 通路转录共激活因子与 PDZ 结合基序 （TAZ） 在肺动脉平滑肌细胞成骨重编程和左心疾病肺动脉高压患者血管钙化中的调节。我们同样使用已建立的冠状动脉上主动脉束带诱导的左心疾病肺动脉高压大鼠模型来检查其作用。

从左心疾病引起的肺动脉高压患者和大鼠中收集肺动脉样本。进行全基因组 RNA 测序，并评估肺动脉钙化。通过 TAZ 和 RUNX2 的成骨信号通过蛋白质生物化学描绘。在体内，在大鼠模型中测试了 CADD522 或维替泊芬抑制 RUNX2 或 TAZ 的治疗潜力。

基因本体术语分析发现，左心疾病肺动脉高压患者肺动脉和大鼠肺中骨化和成骨细胞分化基因（包括 RUNX2）显著富集。肺动脉钙化在患者和大鼠中均明显。TAZ 和 RUNX2 在患者和大鼠的肺动脉平滑肌细胞中均上调和激活。免疫共沉淀显示 RUNX2 与 TAZ 在肺动脉平滑肌细胞中的直接相互作用。TAZ 抑制或敲低降低了 RUNX2 的丰度，这是由于 RUNX2 蛋白降解加速而不是从头合成减少。在大鼠模型中，抑制 TAZ 或 RUNX2 可减轻肺动脉钙化、远端肺血管重塑和肺动脉高压的发展。

左心疾病引起的肺动脉高压与肺动脉钙化有关，肺动脉钙化是由 TAZ 依赖性 RUNX2 稳定驱动的，导致肺动脉平滑肌细胞成骨重编程。TAZ-RUNX2 轴可能在左心疾病引起的肺动脉高压中作为治疗靶点。