Kv7.4 channel is a key regulator of vascular inflammation and remodeling in neointimal hyperplasia and abdominal aortic aneurysms

Abstract

Inflammation has recently emerged as an important contributor for cardiovascular disease development and participates pivotally in the development of neointimal hyperplasia and abdominal aortic aneurysms (AAA) formation. Kv7.4/KCNQ4, a K⁺ channel, is one of the important regulators of vascular function but its role in vascular inflammation is unexplored. Here, we showed that the expression of Kv7.4 channel was elevated in the neointima and AAA tissues from mice and humans. Genetic deletion or pharmacological inhibition of Kv7.4 channel in mice alleviated neointimal hyperplasia and AAA formation via downregulation of a set of vascular inflammation-related genes, matrix metalloproteinases (MMP) 2/9, and intercellular adhesion molecule (ICAM-1). Furthermore, genetic deletion or inhibition of Kv7.4 channel suppressed the activation of tumor necrosis factor receptor 1 (TNFR1)-nuclear factor (NF)-κB signaling pathway via blockade of interaction between TNFR1 and TNFR1-associated death domain protein (TRADD) in vascular smooth muscle cells (VSMCs). Knockdown of Kv7.4 in vivo identified VSMC-expressed Kv7.4 as a major factor in vascular inflammation. Collectively, our findings suggest that Kv7.4 channel aggravates vascular inflammatory response, which promotes the neointimal hyperplasia and AAA formation. Inhibition of Kv7.4 channel may be a novel therapeutic strategy for vascular inflammatory diseases.

Keywords: Kv7.4 channels; Neointimal hyperplasia; TNFR1 signaling; Vascular inflammation; Vascular smooth muscle cells.