Targeting the KCa3.1 channel suppresses diabetes-associated atherosclerosis via the STAT3/CD36 axis

Background: In diet-induced arterial atherosclerosis, increased KCa3.1 channel was associated with atherosclerotic plaque progression and instability. Macrophages are involved in the formation of atherosclerotic plaques, and the release of inflammatory cytokines and oxygen free radicals promotes plaque progression. However, whether the macrophage KCa3.1 channel facilitates diabetes-accelerated atherosclerosis is still unclear. This study investigated atherosclerotic plaque in ApoE(-/-) mice regulated by the KCa3.1 channel.Methods and Results: In vivo, blocking KCa3.1channel inhibit the development of the atherosclerotic lesion in diabetic ApoE(-/-) mice fed with a high-fat diet. In vitro, upregulation of KCa3.1 channel level occurred in RAW264.7 cells treated with HG plus ox-LDL in a time-dependent manner. Blocking KCa3.1 significantly reduced the uptake of ox-LDL in mice peritoneal macrophages. Further studies indicated the KCa3.1 siRNA and TRAM-34 (KCa3.1 inhibitor) attenuated the scavenger receptor CD36 expression via inhibiting STAT3 phosphorylation.Conclusion: Blockade of macrophage KCa3.1 channel inhibit cellular oxidized low-density lipoprotein accumulation and decrease proinflammation factors expression via STAT3/CD36 axis. This study provided a novel therapeutic target to reduce the risk of atherosclerosis development in diabetic patients.

Automated summary

Blocking the KCa3.1 channel in macrophages inhibits the development of atherosclerotic lesions in diabetic ApoE(-/-) mice fed with a high-fat diet. This inhibition is achieved by reducing the uptake of oxidized low-density lipoproteins and decreasing the expression of proinflammatory factors through the STAT3/CD36 axis. This study provides insight into a potential therapeutic target for reducing the risk of atherosclerosis in diabetic patients.