Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Wihuri Research Institute, Helsinki, Finland.
Pharmacol Ther. 2019 Jul;199:91-110. doi: 10.1016/j.pharmthera.2019.03.008. Epub 2019 Mar 12.
Mast cells are tissue-resident cells, which have been proposed to participate in various inflammatory diseases, among them the cardiovascular diseases (CVDs). For mast cells to be able to contribute to an inflammatory process, they need to be activated to exocytose their cytoplasmic secretory granules. The granules contain a vast array of highly bioactive effector molecules, the neutral protease tryptase being the most abundant protein among them. The released tryptase may act locally in the inflamed cardiac or vascular tissue, so contributing directly to the pathogenesis of CVDs. Moreover, a fraction of the released tryptase reaches the systemic circulation, thereby serving as a biomarker of mast cell activation. Actually, increased levels of circulating tryptase have been found to associate with CVDs. Here we review the biological relevance of the circulating tryptase as a biomarker of mast cell activity in CVDs, with special emphasis on the relationship between activation of mast cells in their tissue microenvironments and the pathophysiological pathways of CVDs. Based on the available in vitro and in vivo studies, we highlight the potential molecular mechanisms by which tryptase may contribute to the pathogenesis of CVDs. Finally, the synthetic and natural inhibitors of tryptase are reviewed for their potential utility as therapeutic agents in CVDs.
肥大细胞是组织驻留细胞，已被提出参与各种炎症性疾病，其中包括心血管疾病（CVDs）。为了使肥大细胞能够参与炎症过程，它们需要被激活以胞吐其细胞质分泌颗粒。颗粒中含有大量高度生物活性的效应分子，其中中性蛋白酶胰蛋白酶是最丰富的蛋白质。释放的胰蛋白酶可能在炎症性心脏或血管组织中局部发挥作用，从而直接导致 CVD 的发病机制。此外，一部分释放的胰蛋白酶到达全身循环，从而作为肥大细胞活化的生物标志物。实际上，已经发现循环胰蛋白酶水平升高与 CVD 相关。在这里，我们回顾了循环胰蛋白酶作为 CVD 中肥大细胞活性的生物标志物的生物学相关性，特别强调了组织微环境中肥大细胞的激活与 CVD 的病理生理途径之间的关系。基于现有的体外和体内研究，我们强调了胰蛋白酶可能有助于 CVD 发病机制的潜在分子机制。最后，我们回顾了胰蛋白酶的合成和天然抑制剂，以探讨它们作为 CVD 治疗剂的潜在用途。
