The Cdc42/Rac1 pathway: a molecular mechanism behind iron-deficiency-driven aortic medial degeneration.

[OBJECTIVE] To elucidate the underlying mechanism of iron deficiency augmented Angiotensin II-induced aortic medial degeneration.

[METHODS] ApoE mice were randomly divided into four groups: normal control group (NC group), Angiotensin II (Ang II) subcutaneous pumped alone Group (Ang II group), iron deficiency (ID) group (ID group) and ID+Ang II group. The survival time, systolic blood pressure (SBP), and aortic medial degeneration (AMD) formation were monitored. Iron deposition in the aortas was assessed using Prussian blue iron staining. The expression of iron metabolism indicators, aortopathies and the cytoskeleton of vascular smooth muscle cells (VSMCs) were analyzed. In an in vitro setting, deferoxamine (DFO) was employed to mimic ID to examine the effects of Ang II on the cytoskeletal and contractile function of VSMCs during ID. Ras-related C3 botulinum toxin substrate 1 (Rac-1) expression was inhibited with EHT1864 to verify the role of Cdc42/Rac1 pathway in this pathological process. Blood samples were collected from 150 patients with aortic dissection (AD) and 60 patients with hypertension who were admitted to the Department of Cardiovascular Surgery at Renmin Hospital of Wuhan University between June 2018 and September 2019. The aortic tissues were obtained during the surgical treatment of Stanford type A AD patients and the heart donor. The iron metabolism status in plasma and aortic tissue was analyzed.

[RESULTS] In vivo experiments revealed that, in comparison to the NC and ID groups, mice in the Ang II and ID+Ang II groups exhibited increased SBP, significantly reduced survival time, and an expanded range of aortic dissection (P < 0.05). ID feeding augmented the Ang II-induced aortopathies. Both in vitro and in vivo results indicated that ID led to diminished expression of phosphorylated myosin light chain (p-MLC) and recombinant Cell Division Cycle Protein 42 (Cdc42) in VSMCs, while Rac-1 expression increased. The clinical sample testing data further confirmed the discovery that individuals diagnosed with AD display ID in both the plasma and the diseased aortas.

[CONCLUSIONS] The Cdc42/Rac1 pathway plays a crucial role in disrupting the cytoskeleton of vascular smooth muscle cells during iron deficiency, which leads to aortic medial degeneration both in vivo and in vitro.