Adenosine kinase inhibition protects mice from abdominal aortic aneurysm via epigenetic modulation of VSMC inflammation.

Abdominal aortic aneurysm (AAA) is a common, serious vascular disease with no effective pharmacological treatment. The nucleoside adenosine plays an important role in modulating vascular homeostasis, which prompted us to determine whether adenosine kinase (ADK), an adenosine metabolizing enzyme, modulates AAA formation via control of the intracellular adenosine level, and to investigate the underlying mechanisms. We used a combination of genetic and pharmacological approaches in murine models of AAA induced by calcium chloride (CaCl2) application or angiotensin II (Ang II) infusion to study the role of ADK in the development of AAA. In vitro functional assays were performed by knocking down ADK with adenovirus-short hairpin RNA in human vascular smooth muscle cells (VSMCs), and the molecular mechanisms underlying ADK function were investigated using RNA-sequencing, isotope tracing, and chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR). The heterozygous deficiency of ADK protected mice from CaCl2- and Ang II-induced AAA formation. Moreover, specific knockout of ADK in VSMCs prevented Ang II-induced AAA formation, as evidenced by reduced aortic extracellular elastin fragmentation, neovascularization, and aortic inflammation. Mechanistically, ADK knockdown in VSMCs markedly suppressed the expression of inflammatory genes associated with AAA formation, and these effects were independent of adenosine receptors. The metabolic flux and ChIP-qPCR results showed that ADK knockdown in VSMCs decreased S-adenosylmethionine (SAM)-dependent transmethylation, thereby reducing H3K4me3 binding to the promoter regions of the genes that are associated with inflammation, angiogenesis, and extracellular elastin fragmentation. Furthermore, the ADK inhibitor ABT702 protected mice from CaCl2-induced aortic inflammation, extracellular elastin fragmentation, and AAA formation. Our findings reveal a novel role for ADK inhibition in attenuating AAA via epigenetic modulation of key inflammatory genes linked to AAA pathogenesis.

Xu J ，Liu Z ，Yang Q ，Ma Q ，Zhou Y ，Cai Y ，Zhao D ，Zhao G ，Lu T ，Ouyang K ，Hong M ，Kim HW ，Shi H ，Zhang J ，Fulton D ，Miller C ，Malhotra R ，Weintraub NL ，Huo Y ... -  《-》

Thymidine Phosphorylase Promotes Abdominal Aortic Aneurysm via VSMC Modulation and Matrix Remodeling in Mice and Humans.

Background: Thymidine phosphorylase (TYMP) promotes platelet activation and thrombosis while suppressing vascular smooth muscle cell (VSMC) proliferation. Both processes are central to the development and progression of abdominal aortic aneurysms (AAAs). We hypothesize that TYMP plays a role in AAA development. Methods: Male wild-type (WT) C57BL/6J and Tymp-/- mice, fed a Western diet (WD) (TD.88137), were subjected to the 4-week Ang II infusion-induced AAA model. AAA progression was monitored by echography and confirmed through necropsy. Whole-body inflammation was assessed using a plasma cytokine array. Mechanistic studies were conducted using TYMP-overexpressing rat VSMC cell lines and primary VSMCs cultured from WT and Tymp-/- mouse thoracic aortas. Histological studies were performed on human AAA and normal aorta samples. Results: Elevated TYMP levels were observed in human AAA vessel walls. While WT mice exhibited a 28.6% prevalence of Ang II infusion-induced AAA formation, Tymp-/- mice were protected. TYMP enhanced MMP2 expression, secretion, and activation in VSMCs, which was inhibited by tipiracil, a selective TYMP inhibitor. Systemically, TYMP promoted proinflammatory cytokine expression, and its absence attenuated TNF-α-induced MMP2 and AKT activation. WT VSMCs treated with platelets lacking TYMP showed a higher proliferation rate than cells treated with WT platelets. Additionally, TYMP increased activated TGFβ1 expression in cultured VSMCs and human AAA vessel walls. In WT VSMCs, TYMP augmented thrombospondin-1 type 1 repeat domain (TSR)-stimulated TGFβ1 signaling, increasing connective tissue growth factor and MMP2 production. TSR also enhanced AKT activation in WT VSMCs but had the opposite effect in Tymp-/- cells. TSR-enhanced MMP2 activation in WT VSMCs was attenuated by LY294002 (a PI3K inhibitor) but not by SB431542 (a TGFβ1 inhibitor); both inhibitors had indiscernible effects on Tymp-/- VSMC. Conclusion: TYMP emerges as a novel regulatory force in vascular biology, influencing VSMC function and inflammatory responses to promote AAA development.

Hong L ，Yue H ，Cai D ，DeHart A ，Toloza-Alvarez G ，Du L ，Zhou X ，Fan X ，Huang H ，Chen S ，Rahaman SO ，Zhuang J ，Li W ... -  《-》

Chronic intermittent hypoxia facilitates the development of angiotensin II-induced abdominal aortic aneurysm in male mice.

Sharma N ，Khalyfa A ，Cai D ，Morales-Quinones M ，Soares RN ，Higashi Y ，Chen S ，Gozal D ，Padilla J ，Manrique-Acevedo C ，Chandrasekar B ，Martinez-Lemus LA ... -  《-》

Disruption of PCSK9 Suppresses Inflammation and Attenuates Abdominal Aortic Aneurysm Formation.

Peng Z ，Lv SJ ，Chen H ，Rao H ，Guo Z ，Wan Q ，Yang J ，Zhang Y ，Liu DP ，Chen HZ ，Wang M ... -  《-》

Nuclear Receptor NR1D1 Regulates Abdominal Aortic Aneurysm Development by Targeting the Mitochondrial Tricarboxylic Acid Cycle Enzyme Aconitase-2.

Sun LY ，Lyu YY ，Zhang HY ，Shen Z ，Lin GQ ，Geng N ，Wang YL ，Huang L ，Feng ZH ，Guo X ，Lin N ，Ding S ，Yuan AC ，Zhang L ，Qian K ，Pu J ... -  《-》