Tumor Necrosis Factor Alpha-Mediated Inflammation and Remodeling of the Extracellular Matrix Underlies Aortic Stiffening Induced by the Common Chemotherapeutic Agent Doxorubicin
Zachary S. Clayton, Vienna E. Brunt, David A. Hutton, Abigail G. Casso, Brian P. Ziemba, Simon Melov, Judith Campisi, Douglas R. Seals
Abstract
Aortic stiffening is a major independent risk factor for cardiovascular diseases, kidney dysfunction, and cognitive impairment. Doxorubicin chemotherapy-treated cancer survivors have greater aortic stiffness relative to healthy controls, but the mechanisms by which doxorubicin induces arterial stiffening are unknown. We tested the hypothesis that doxorubicin increases aortic stiffness by increasing intrinsic mechanical wall stiffness due to proinflammatory signaling-induced adverse structural changes, including collagen deposition (fibrosis), elastin fragmentation, and formation of AGEs (advanced glycation end products). In vivo aortic stiffness (assessed via aortic pulse wave velocity), aortic intrinsic wall stiffness (ex vivo assessment of elastic modulus), and potential underlying mechanisms were assessed 4 weeks after administration of doxorubicin (10 mg/kg) or vehicle (saline) in young adult male C57BL6/J mice. Aortic pulse wave velocity increased by ~30% following doxorubicin (pre: 341±18 versus post: 431±28 cm/s, mean±SEM, P =0.001) and aortic elastic modulus was ~100% higher following doxorubicin (5438±445 kPa) versus vehicle (2659±433 kPa; P =0.003). These effects of doxorubicin 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. Doxorubicin increased aortic proinflammatory cytokines ( P =0.03) without a compensatory increase in the anti-inflammatory cytokine interleukin-10. Direct ex vivo exposure of aorta rings to doxorubicin mimicked the increase in aortic elastic modulus observed in vivo with doxorubicin, whereas TNF-α (tumor necrosis factor-α) inhibition prevented this response. Doxorubicin 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 TNF-α-dependent vascular inflammation.