Impairment of autophagy in endothelial cells prevents shear-stress-induced increases in nitric oxide bioavailability

Author:

Bharath Leena P.12,Mueller Robert1,Li Youyou1,Ruan Ting1,Kunz David1,Goodrich Rebekah1,Mills Tyler1,Deeter Lance1,Sargsyan Ashot23,Anandh Babu Pon Velayutham1,Graham Timothy E.23,Symons J. David12

Affiliation:

1. College of Health, University of Utah, Salt Lake City, UT 84112, USA.

2. Division of Endocrinology, Metabolism, and Diabetes, University of Utah School of Medicine, Salt Lake City, UT 84112-9003, USA.

3. Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112, USA.

Abstract

Autophagy is a lysosomal catabolic process by which cells degrade or recycle their contents to maintain cellular homeostasis, adapt to stress, and respond to disease. Impairment of autophagy in endothelial cells studied under static conditions results in oxidant stress and impaired nitric oxide (NO) bioavailability. We tested the hypothesis that vascular autophagy is also important for induction of NO production caused by exposure of endothelial cells to shear stress (i.e., 3 h × ≈20 dyn/cm2). Atg3 is a requisite autophagy pathway mediator. Control cells treated with non-targeting control siRNA showed increased autophagy, reactive oxygen species (ROS) production, endothelial NO synthase (eNOS) phosphorylation, and NO production upon exposure to shear stress (p < 0.05 for all). In contrast, cells with >85% knockdown of Atg3 protein expression (via Atg3 siRNA) exhibited a profound impairment of eNOS phosphorylation, and were incapable of increasing NO in response to shear stress. Moreover, ROS accumulation and inflammatory cytokine production (MCP-1 and IL-8) were exaggerated (all p < 0.05) in response to shear stress. These findings reveal that autophagy not only plays a critical role in maintaining NO bioavailability, but may also be a key regulator of oxidant–antioxidant balance and inflammatory–anti-inflammatory balance that ultimately regulate endothelial cell responses to shear stress.

Publisher

Canadian Science Publishing

Subject

Physiology (medical),Pharmacology,General Medicine,Physiology

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