Krüppel‐Like Factor 15/Interleukin 11 Axis‐Mediated Adventitial Remodeling Depends on Extracellular Signal‐Regulated Kinases 1 and 2 Activation in Angiotensin II–Induced Hypertension

BACKGROUND: Adventitial remodeling is a pathological hallmark of hypertension that results in target organ damage. Activated adventitial fibroblasts have emerged as critical regulators in this process, but the precise mechanism remains unclear. METHODS AND RESULTS: Interleukin 11 (IL‐11) knockout and wild‐type mice were subjected to angiotensin II (Ang II) infusion to establish models of hypertension‐associated vascular remodeling. IL‐11 mRNA and protein were increased especially in the adventitia in response to Ang II. Compared with wild‐type mice, Ang II–treated IL‐11 knockout mice showed amelioration of vascular hypertrophy, adventitial fibrosis, macrophage infiltration, and inflammatory factor expression. Recombination mouse IL‐11 exacerbated adventitial fibrosis in Ang II–infused wild‐type mice. Interestingly, IL‐11 neutralizing antibody attenuated adventitial fibrosis, macrophage infiltration, and inflammatory factor expression after Ang II infusion for 7 days. Mechanistically, in primary cultured adventitial fibroblasts, Krüppel‐like factor 15 negatively regulated Ang II–induced IL‐11 expression. Ang II increased extracellular signal‐regulated kinases 1 and 2 activation, especially in adventitia, and caused biphasic extracellular signal‐regulated kinases 1 and 2 activation in adventitial fibroblasts. A rapid and early activation increased IL‐11 production through decreasing Krüppel‐like factor 15 expression, which, in turn, induced the second extracellular signal‐regulated kinases 1 and 2 activation, resulting in posttranscriptional profibrotic gene expression. CONCLUSIONS: These results demonstrate that extracellular signal‐regulated kinases 1 and 2 activation is important for Krüppel‐like factor 15–mediated IL‐11 expression in adventitial fibroblasts to promote adventitial remodeling in Ang II–induced hypertension. Therefore, targeting the Krüppel‐like factor 15/IL‐11 axis might serve as a new therapeutic strategy for vascular diseases.