Study Reveals How Dkk3 Triggers Smooth Muscle Cell Transformation In Aortic Aneurysm

Background

Abdominal aortic aneurysm (AAA) is simply a life-threatening vascular upset that chiefly affects aged males. It often develops asymptomatically, yet aneurysm rupture tin lead to accelerated fatality. Currently, nary effective pharmacological therapies are disposable to halt aliases reverse AAA progression. Previous studies person highlighted nan phenotypic switching of vascular soft musculus cells (VSMCs) arsenic a cardinal arena successful AAA pathogenesis, though nan molecular mechanisms governing this process stay incompletely understood. Notably, nan secreted glycoprotein DKK3 has precocious been associated pinch aggregate cardiovascular diseases, wherever it influences insubstantial regeneration and upregulates matrix metalloproteinases (MMPs). However, nan imaginable domiciled and mechanistic publication of DKK3 successful AAA had not yet been elucidated.

Research progress

In bid to observe nan changes of DKK3 during AAA developmen t and to elucidate its functional domiciled and underlying mechanisms, nan teams of Associate Prof. Baoqi Yu, Prof. Aijuan Qu from nan Basic Medical College of Capital Medical University and Prof. Qingbo Xu from The First Affiliated Hospital, Zhejiang University School of Medicine started an in-depth cooperation. The researchers identified a displacement successful VSMC subpopulations successful AAA, characterized by a diminution successful contractile VSMCs and an description of modulated VSMCs exhibiting precocious DKK3 expression. DKK3 was markedly upregulated successful aortic aneurysm tissues and was predominantly localized wrong VSMCs.

In an angiotensin II (Ang II)-induced rodent exemplary of AAA, some systemic DKK3 knockout and VSMC-specific DKK3 knockdown markedly attenuated aortic dilation, reduced nan incidence and rupture rates of AAA, and suppressed elastin degradation. Mechanistically, DKK3 deficiency maintained nan contractile phenotype of VSMCs, downregulated MMP expression, and enhanced VSMC contractility. Furthermore, DKK3 knockout reversed Ang II-induced suppression of nan TGF-β signaling pathway, elevated TGFβ3 expression, and promoted Smad2/3 phosphorylation. Further investigation revealed that DKK3 modulates nan TGF-β-Smad2/3 signaling pathway done nan transcription facet ATF6. ATF6 knockdown accrued TGFβ3 level and VSMC contractile markers, whereas curen pinch nan ATF6 agonist AA147 counteracted nan effects of DKK3 deficiency and promoted VSMC phenotype switching.
This study demonstrates that DKK3 promotes AAA progression done TGFβ3-Smad2/3 signaling pathway mediated pinch ATF6, driving VSMC phenotype switching toward a synthetic state, enhancing MMP production, and accelerating elastin degradation. These findings place DKK3 arsenic a imaginable therapeutic target for maintaining VSMC homeostasis successful AAA.

Future prospects

Current objective guidance of AAA relies chiefly connected surgical intervention, pinch nary effective supplier therapies disposable to reverse illness progression. This study elucidates a caller system by which DKK3 promotes AAA done nan ATF6-TGFβ3-Smad2/3 axis, regulating VSMC phenotypic transformation. Inhibition aliases blockade of DKK3 whitethorn truthful correspond a promising therapeutic strategy for AAA. These results not only beforehand our knowing of AAA pathogenesis but besides propose DKK3 arsenic a imaginable diagnostic biomarker and therapeutic target.