Abstract
Background and purpose:
Salvianolic acid B (SalB) is effective for treating cardiovascular diseases. However, its therapeutic molecular mechanisms remain unclear. Mechanosensitive Piezo1 channels play important roles in vascular biology, although its pharmacological properties are poorly defined. Here, we aimed to identify novel Piezo1 inhibitors and gain insights into their mechanisms of action.
Experimental approach:
Intracellular Ca2+ ions were measured in human umbilical vein endothelial cells (HUVECs), murine liver endothelial cells (MLECs), THP-1 and RAW264.7 cell lines, and bone marrow-derived macrophages (BMDMs). Isometric tensions in mouse thoracic aorta were recorded. Shear-stress assays with HUVECs were conducted. Patch-clamp recordings with mechanical stimulation were performed with HUVECs in whole-cell mode. Foam cell formation was induced by treating BMDMs with oxidised low-density lipoprotein (oxLDL). Atherosclerotic plaque assays were performed with Ldlr-/- and Piezo1 genetically depleted mice on a high-fat diet.
Key results:
We discovered that SalB inhibited Yoda1-induced Ca2+ influx in HUVECs and MLECs. Similar results were observed in macrophage cell lines and BMDMs. Furthermore, we demonstrated that SalB inhibited Yoda1 and mechanically activated currents. SalB restrained Yoda1-induced aortic ring relaxation and inhibited HUVECs alignment in the direction of shear stress. Additionally, we found that Yoda1 enhanced the formation of foam cells, which was reversed by SalB and SalB inhibited the formation of atherosclerotic plaques and was insensitive to Piezo1 genetically depletion.
Conclusion and implications:
Our study provides novel mechanistic insights into the inhibitory role of SalB against Piezo1 channels and improves our understanding of SalB in preventing atherosclerotic lesions.
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