利钠肽受体C（NPR-C）缺乏通过损害线粒体稳态引发高盐诱导的胸主动脉夹层。

Wei Jin-Qiu, Yang Yi, Zhai Wen-Hui, Zhao Jia-Jia, Yang Yi-Hang, Kang Yuan-Yuan, Huang Qi-Fang, Zhang Wei, Rong Wu-Wei, Deng Qian-Wan, Chen Jing, Ye Xiao-Fei, Gao Ping-Jin, Wang Zhe, Li Xiao-Dong, Wang Ji-Guang

Department of Cardiovascular Medicine, Department of Hypertension, Ruijin Hospital and State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Ruijin 2nd Road 197, Shanghai 200025, China.

Department of Cardiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Cardiac Electrophysiology and Arrhythmia, Shandong First Medical University, 16766 Jinshi Road, Jinan 250014, China.

Cardiovasc Res. 2025 Jul 8;121(7):1121-1134. doi: 10.1093/cvr/cvaf085.

AIMS

Thoracic aortic dissection (TAD) is a highly fatal disease lacking effective pharmacologic interventions in clinical practice. Emerging evidence indicates that the natriuretic peptide receptor C (NPR-C) plays a crucial role in the regulation of cardiovascular diseases. However, the precise involvement of NPR-C in TAD remains elusive. In this study, the role and molecular mechanisms of NPR-C in the pathogenesis of TAD were investigated.

METHODS AND RESULTS

Through integrated analyses of human TAD transcriptome and single-cell sequencing data sets, we identified that NPR-C was downregulated in the aortas of acute TAD patients and in beta-aminopropionitrile (BAPN)-treated mice. Intriguingly, vascular smooth muscle cell (VSMC)-specific NPR-C knockout (NPR-CSMKO) mice, rather than endothelial cell-specific NPR-C knockout mice, developed TAD after treated with angiotensin II (Ang II) plus high salt diet (HSD), but not Ang II alone. Loss of NPR-C function promoted extracellular matrix degeneration, VSMCs apoptosis, and inflammation. RNA-sequencing analysis revealed that mitochondrial fatty acid oxidation (FAO) genes were significantly downregulated in the thoracic aortas of NPR-CSMKO mice treated with Ang II plus HSD. Notably, the expression of HADHB, a subunit of mitochondrial trifunctional protein (MTP) responsible for FAO, was obviously decreased in NPR-CSMKO mice treated with Ang II plus HSD. Mechanistically, knockdown of NPR-C activated ERK1/2 pathway, which decreased the expression and activity of peroxisome proliferator-activated receptor γ (PPARγ) and inhibited HADHB expression. Furthermore, NPR-C agonist, C-ANP4-23, mitigated the progression of TAD in BAPN-treated mice. Activation of MTP by spermidine (SPD) effectively prevented TAD formation in NPR-CSMKO mice treated with Ang II plus HSD.

CONCLUSION

Our data highlight a critical role of HSD in triggering TAD and a previously unrecognized role of NPR-C that protects against TAD through regulating mitochondrial homeostasis. Therefore, NPR-C activation and SPD supplementation could be new prevention and treatment strategies for TAD.

目的

胸主动脉夹层（TAD）是一种临床实践中缺乏有效药物干预的高致死性疾病。新出现的证据表明，利钠肽受体C（NPR-C）在心血管疾病的调节中起关键作用。然而，NPR-C在TAD中的具体作用仍不清楚。在本研究中，我们探讨了NPR-C在TAD发病机制中的作用及其分子机制。

方法与结果

通过对人类TAD转录组和单细胞测序数据集的综合分析，我们发现NPR-C在急性TAD患者的主动脉以及β-氨基丙腈（BAPN）处理的小鼠主动脉中表达下调。有趣的是，血管平滑肌细胞（VSMC）特异性NPR-C基因敲除（NPR-CSMKO）小鼠，而非内皮细胞特异性NPR-C基因敲除小鼠，在接受血管紧张素II（Ang II）加高盐饮食（HSD）处理后发生了TAD，但单独使用Ang II处理时未发生。NPR-C功能丧失促进了细胞外基质退变、VSMC凋亡和炎症反应。RNA测序分析显示，在用Ang II加HSD处理的NPR-CSMKO小鼠的胸主动脉中，线粒体脂肪酸氧化（FAO）基因显著下调。值得注意的是，在用Ang II加HSD处理的NPR-CSMKO小鼠中，负责FAO的线粒体三功能蛋白（MTP）的一个亚基HADHB的表达明显降低。机制上，敲低NPR-C激活了ERK1/2通路，这降低了过氧化物酶体增殖物激活受体γ（PPARγ）的表达和活性，并抑制了HADHB的表达。此外，NPR-C激动剂C-ANP4-23减轻了BAPN处理小鼠的TAD进展。亚精胺（SPD）激活MTP有效地预防了用Ang II加HSD处理的NPR-CSMKO小鼠的TAD形成。