Tetramethylpyrazine Alleviates Endothelial Glycocalyx Degradation and Promotes Glycocalyx Restoration via TLR4/NF-κB/HPSE1 Signaling Pathway During Inflammation

Abstract

Tetramethylpyrazine (TMP), a Chinese traditional herbal extraction widely used in treating cardiovascular diseases, could attenuate vascular endothelial injuries, but the underlying mechanism remains incomprehensive. Vascular glycocalyx coating on the endothelium would be damaged and caused endothelial dysfunction in the inflammatory microenvironment, which was the initial factor of morbidity of many vascular diseases, such as atherosclerosis (AS). Here, we thoroughly investigated the molecular mechanism of TMP on vascular endothelial glycocalyx in the LPS-induced inflammatory model both in vitro and in vivo. Results showed that pretreatment with TMP significantly inhibited glycocalyx degradation and monocytes adhesion to the endothelial process. Moreover, TMP pretreatment inhibited the expression of HPSE1 (a major degrading enzyme of endothelial glycocalyx), Toll-like receptor 4 (TLR4), and the translocation of nuclear factor kappa B p65 (NF-κB p65). We were utilized withTLR4 siRNA, NF-κB inhibitor, and HPSE1 overexpression analysis confirmed TMP’s protection on endothelial glycocalyx injury, which further contributed to the monocyte-endothelial adhesion process. It was indicated that TMP might suppress glycocalyx degradation through TLR4/NF-κB/HPSE1 signaling pathway. Taken together, our results enriched the occurrence molecular mechanism of glycocalyx shedding and molecular regulation mechanism of TMP in protecting integrity of the glycocalyx structure during inflammation. As TMP is currently used in clinical applications, it may be considered a novel strategy against atherosclerosis through its ability to protect endothelial glycocalyx.

Tetramethylpyrazine and paeoniflorin combination (TMP-PF) alleviates atherosclerosis progress by reducing hyperlipemia and inhibiting plaque angiogenesis via the NR4A1/VEGFR2 pathway

“…In the present study, TMP-PF alleviated atherosclerosis progress by reducing hyperlipemia and inhibiting plaque angiogenesis, which partially clarified the anti-atherosclerotic effects of the Rhizoma Chuanxiong-Radix Paeoniae Rubra herb pair. Previous studies showed that TMP had anti-inflammatory, anti-apoptotic, anti-oxidative, anti-platelet and endothelial cells protection effects in the treatment of cardio-cerebrovascular diseases, such as atherosclerosis, myocardial ischemia and hypertension [26], it was capable of regulating lipid levels and attenuating oxidative stress, inflammatory responses and endoplasmic reticulum stress in gestational diabetes mellitus model mice [27]; TMP suppressed endothelial glycocalyx degradation and protected integrity of glycocalyx structure during inflammation, which might be considered a novel strategy in the treatment of atherosclerosis [28]. Previous studies also showed that PF had anti-hyperglycaemic, anti-inflammatory, anti-oxidative and anti-apoptotic effects, and it attenuated ox-LDL-induced injury in endothelial cells by inhibiting apoptosis and activating autophagy [29],…”

Interleukin-6 drives endothelial glycocalyx damage in COVID-19 and bacterial sepsis

“…However, upstream of HPSE upregulation and release, only a few specific signalling pathways have been identified, all of which are pathophysiologically relevant in sepsis. These include the angiopoietin-1/Tie2 ligand receptor system, tumor necrosis factor (TNF)-alpha/ TNF receptor signalling and toll-like receptor (TLR)-2 and − 4 signalling [2,3,[12][13][14].…”