Tumor Necrosis Factor Alpha-Mediated Inflammation and Remodeling of the Extracellular Matrix Underlies Aortic Stiffening Induced by the Common Chemotherapeutic Agent Doxorubicin.
Tumor Necrosis Factor Alpha-Mediated Inflammation and Remodeling of the Extracellular Matrix Underlies Aortic Stiffening Induced by the Common Chemotherapeutic Agent Doxorubicin.
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DOI：
10.1161/hypertensionaha.120.16759
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发表时间：
2021-05-05
期刊：
影响因子：
--
通讯作者：
Seals DR
中科院分区：
文献类型：
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作者：
Clayton ZS;Brunt VE;Hutton DA;Casso AG;Ziemba BP;Melov S;Campisi J;Seals DR
Aortic stiffening is a major independent risk factor for cardiovascular diseases, kidney dysfunction and cognitive impairment. Doxorubicin (DOXO) chemotherapy-treated cancer survivors have greater aortic stiffness relative to healthy controls, but the mechanisms by which DOXO induces arterial stiffening are unknown. We tested the hypothesis that DOXO increases aortic stiffness by increasing intrinsic mechanical wall stiffness due to pro-inflammatory signaling-induced adverse structural changes, including collagen deposition (fibrosis), elastin fragmentation and/or formation of advanced glycation end products (AGEs). In vivo aortic stiffness (assessed via aortic pulse-wave velocity [PWV]), aortic intrinsic wall stiffness (ex vivo assessment of elastic modulus [EM]) and potential underlying mechanisms were assessed 4 weeks after administration of DOXO (10 mg/kg) or vehicle (saline) in young adult male C57BL6/J mice. Aortic PWV increased by ~30% following DOXO (Pre: 341±18 vs. Post: 431±28 cm/s, mean±SEM, P=0.001) and aortic EM was ~100% higher following DOXO (5438±445 kPa) vs. vehicle (2659±433 kPa) (P=0.003). These effects of DOXO were associated with an ~3-fold greater formation of AGEs (P=0.01) and an ~50% reduction in elastin (P=0.01), whereas collagen deposition was unaffected. DOXO increased aortic pro-inflammatory cytokines (P=0.03) without a compensatory increase in the anti-inflammatory cytokine interleukin-10. Direct ex vivo exposure of aorta rings to DOXO mimicked the increase in aortic EM observed in vivo with DOXO, whereas tumor necrosis factorα (TNFα) inhibition prevented this response. DOXO induces aortic stiffening in vivo due in part to an increase in intrinsic wall stiffness associated with elastin degradation and AGES formation and mediated by TNFα-dependent vascular inflammation. We show that doxorubicin-induced aortic stiffening is mediated by an increase in intrinsic mechanical wall stiffness associated with elastin degradation and accelerated formation of advanced glycation end products linked to tumor necrosis factor alpha-related vascular inflammation. Our results identify several potential therapeutic targets for reducing cardiovascular risk associated with aortic stiffening in cancer patients treated with anthracycline-based chemotherapy.
