Nature cardiovascular research最新文献

Thoracic and abdominal aortic aneurysm poses a substantial mortality risk in adults, yet many of its underlying factors remain unidentified. Here, we identify mitochondrial nicotinamide adenine dinucleotide (NAD)⁺ deficiency as a causal factor for the development of aortic aneurysm. Multiomics analysis of 150 surgical aortic specimens indicated impaired NAD⁺ salvage and mitochondrial transport in human thoracic aortic aneurysm, with expression of the NAD⁺ transporter SLC25A51 inversely correlating with disease severity and postoperative progression. Genome-wide gene-based association analysis further linked low SLC25A51 expression to risk of aortic aneurysm and dissection. In mouse models, smooth muscle-specific knockout of Nampt, Nmnat1, Nmnat3, Slc25a51, Nadk2 and Aldh18a1, genes involved in NAD⁺ salvage and transport, induced aortic aneurysm, with Slc25a51 deletion producing the most severe effects. Using these models, we suggest a mechanism that may explain the disease pathogenesis: the production of type III procollagen during aortic medial matrix turnover imposes a high demand for proline, an essential amino acid component of collagen. Deficiency in the mitochondrial NAD⁺ pool, regulated by NAD⁺ salvage and transport, hinders proline biosynthesis in mitochondria, contributing to thoracic and abdominal aortic aneurysm.

Loss-of-function mutations in NOTCH1 were previously linked to thoracic aortopathy, a condition for which non-surgical treatment options are limited. Based on clinical proteome analysis, we hypothesized that mitochondrial fusion and biogenesis in aortic smooth muscle cells (SMCs) are crucial for regulating the progression of NOTCH1-related aortopathy. Here we demonstrate that SMC-specific Notch1 knockout mice develop aortic pathology, including stiffening, dilation and focal dissection. These changes are accompanied by decreased expression of MFN1/2 and TFAM, mirroring findings in human patients. SMC-specific deletion of Mfn1 and/or Mfn2 genes recapitulates the aortopathy seen in Notch1-deficient mice. Prophylactic or therapeutic approaches aimed at increasing mitochondrial DNA copy number, either through AAV-mediated overexpression of Mfn1/2 or oral treatment with mitofusion activators teriflunomide or leflunomide, help mitigate or slow the progression of aortopathy in SMC-Notch1^-/- mice. Our findings provide a molecular framework for exploring pharmacological interventions to restore mitochondrial function in NOTCH1-related aortopathy.

Beyond dyslipidemia, inflammation contributes to the development of atherosclerosis. However, intrinsic factors that counteract vascular inflammation and atherosclerosis remain scarce. Here we identify insulin-like growth factor binding protein 6 (IGFBP6) as a homeostasis-associated molecule that restrains endothelial inflammation and atherosclerosis. IGFBP6 levels are significantly reduced in human atherosclerotic arteries and patient serum. Reduction of IGFBP6 in human endothelial cells by siRNA increases inflammatory molecule expression and monocyte adhesion. Conversely, pro-inflammatory effects mediated by disturbed flow (DF) and tumor necrosis factor (TNF) are reversed by IGFBP6 overexpression. Mechanistic investigations further reveal that IGFBP6 executes anti-inflammatory effects directly through the major vault protein (MVP)-c-Jun N-terminal kinase (JNK)/nuclear factor kappa B (NF-κB) signaling axis. Finally, IGFBP6-deficient mice show aggravated diet- and DF-induced atherosclerosis, whereas endothelial-cell-specific IGFBP6-overexpressing mice protect against atherosclerosis. Based on these findings, we propose that reduction of endothelial IGFBP6 is a predisposing factor in vascular inflammation and atherosclerosis, which can be therapeutically targeted.