AMP‐activated protein kinase regulates glycocalyx impairment and macrophage recruitment in response to low shear stress

Abstract

Low shear stress (LSS) increases degradation of the endothelial glycocalyx, leading to production of endothelial inflammation and atherosclerosis. However, the underlying mechanisms of how LSS diminishes the endothelial glycocalyx remain unclear. We showed that LSS inactivated AMPK, enhanced Na+‐H+ exchanger (NHE)1 activity, and induced glycocalyx degradation. Activation of AMPK prevented LSS‐induced NHE1 activity and endothelial glycocalyx impairment. We further identified hyaluronidase 2 (HYAL2) as a mediator of endothelial glycocalyx impairment in HUVECs exposed to LSS. Inactivation of AMPK by LSS up‐regulates the activity of HYAL2, which acts downstream of NHE1. We characterized a left common carotid artery partial ligation (PL) model of LSS in C57BL/6 mice. The results showed decreased expression of hyaluronan (HA) in the endothelial glycocalyx and decreased thickness of the endothelial glycocalyx in PL mice. Pharmacological activation of AMPK by ampkinone not only attenuated glycocalyx impairment due to HA degradation but also blocked vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 expression increase and macrophage recruitment in the endothelia of PL mice. Our results revealed that AMPK dephosphorylation induced by LSS activates NHE1 and HYAL2 to promote HA degradation and glycocalyx injury, which may contribute to endothelial inflammatory reaction and macrophage recruitment.—Zhang, J., Kong, X., Wang, Z., Gao, X., Ge, Z., Gu, Y., Ye, P., Chao, Y., Zhu, L., Li, X., Chen, S. AMP‐activated protein kinase regulates glycocalyx impairment and macrophage recruitment in response to low shear stress. FASEB J. 33, 7202–7212 (2019). http://www.fasebj.org

Endothelial glycocalyx damage as a systemic inflammatory microvascular endotheliopathy in COVID-19

“…Indeed, it has been previously shown that a smoking cessation program using varenicline or nicotine replacement therapy for 3 months resulted in a decrease of carbon monoxide (CO), oxidative stress, arterial stiffness, and restored the endothelial glycocalyx [ 45 ]. Physical inactivity induces systemic low shear stress in the body, and it has been demonstrated that AMP-activated protein kinase regulates glycocalyx impairment due to hyaluronan degradation and macrophage recruitment in response to low shear stress in a mice common carotid artery ligation model [ 46 ]. Moreover, the vascular endothelial glycocalyx is perturbed by various unfavorable disease conditions, including dehydration, acute infectious disease [ 47 ], trauma [ 48 ], sepsis [ 49 ], ARDS [ 50 ], preeclampsia [ 51 ], gestational diabetes mellitus [ 52 ], and chronic disease conditions, such as hypertension, diabetes [ 19 , 53 ], chronic kidney disease [ 54 ], atherosclerosis [ [55] , [56] , [57] , [58] , [59] , [60] ], stroke [ 61 , 62 ], dementia [ 63 ], microvascular angina [ 64 ], ACS [ 65 ], and heart failure [ 66 ].…”

Protective Activities of Dendrobium huoshanense C. Z. Tang et S. J. Cheng Polysaccharide against High-Cholesterol Diet-Induced Atherosclerosis in Zebrafish

“…The parallel-plate flow chamber (Shanghai Medical Instrument School, Shanghai, China) was performed to impose an LSS on the monolayer of EA.hy 926 cells as previously described by Zhang et al [ 24 ]; the laminar with tiled EA.hy 926 cells were placed on the chamber and obtained an LSS (3 dyn/cm 2 ) in the incubator at 37°C for 30 min. The cells under static without flow were used as control.…”

Mechanism of Vascular Endothelial Dysfunction Causing Arteriosclerosis: Vascular Endothelial Glycocalyx

“…In addition, vascular endothelial glycocalyx damage is also caused by a decrease in shear stress, and it is known that vascular endothelial glycocalyx damage is responsible for vulnerable plaque formation in the area of arterial bifurcations and strong flexion. In vivo and in vitro models of decreased shear stress caused vascular endothelial glycocalyx degradation, and plaque formation was strongly induced at the same site 19 .…”

“…Increasing glycocalyx damage results in further thinning of the vascular endothelial glycocalyx layer. It is known that the reduction of shear stress also causes thinning of vascular endothelial glycocalyx through the inactivation of AMP-activated protein kinase (AMPK) and the activation of hyaluronidase 2 which induces shedding of hyaluronan and exfoliates vascular endothelial glycocalyx 19 . Syndecan-1 is known as a molecule that regulates shear stress-related signals.…”