Genetic Dissection of the Impact of miR-33a and miR-33b during the Progression of Atherosclerosis

Abstract

SUMMARY As an important regulator of macrophage cholesterol efflux and HDL biogenesis, miR-33 is a promising target for treatment of atherosclerosis, and numerous studies demonstrate that inhibition of miR-33 increases HDL levels and reduces plaque burden. However, important questions remain about how miR-33 impacts atherogenesis, including whether this protection is primarily due to direct effects on plaque macrophages, or regulation of lipid metabolism in the liver. We demonstrate that miR-33 deficiency in Ldlr−/− mice promotes obesity, insulin-resistance and hyperlipidemia, but does not impact plaque development. We further assess how loss of miR-33 or addition of miR-33b in macrophages and other hematopoietic cells impact atherogenesis. Macrophage-specific loss of miR-33 decreases lipid accumulation and inflammation under hyperlipidemic conditions, leading to reduced plaque burden. Therefore, the pro-atherogenic effects observed in miR-33 deficient mice are likely counterbalanced by protective effects in macrophages, which may be the primary mechanism through which anti-miR-33 therapies reduce atherosclerosis.

LncRNA NEXN-AS1 attenuates proliferation and migration of vascular smooth muscle cells through sponging miR-33a/b

“…29,31 Moreover, miR-33a/ b silencing was reported to perform atheroprotective effects through regulating cholesterol efflux, lipid accumulation and macrophage inammation. 19,30,32 Subsequently, we rstly manifested that NEXN-AS1 acted as molecular sponges for miR-33a and miR-33b. Based on the above, our study continued from this hypothesis that NEXN-AS1 regulated the proliferation and migration of VSMCs via miR-33a and miR-33b.…”

“…MiR-33 family, which consists of miR-33a and miR-33b, has been identied to play a pro-atherogenic role via various regulatory mechanisms. 19,20 However, whether miR-33a/b inuence VSMC proliferation and migration has not been reported. In the present study, our data rstly demonstrated that ox-LDL reduced NEXN-AS1 expression and NEXN-AS1 overexpression mitigated the proliferation and migration of ox-LDL-induced HA-VSMCs.…”

Downregulation of miR‐33b promotes non‐small cell lung cancer cell growth through reprogramming glucose metabolism miR‐33b regulates non‐small cell lung cancer cell growth

“…32 In our study, the interaction between LDHA and miR-33b was verified by luciferase reporter assay. 36 These factors should also be considered to maximize the therapeutic utility of miR-33b. Several signaling pathways have been previously identified to regulate LDHA, including JMJD2A-LDHA (Jumonji C domain 2A-Lactate dehydrogenase A) and KLF4/LDHA (Krüppel-like factor 4-Lactate dehydrogenase A) pathways, which are crucial to glycolysis regulation in cancer.…”

Genetic deficiency or pharmacological inhibition of miR-33 protects from kidney fibrosis

“…miR-33 inhibitors have previously been used as a strategy for raising circulating HDL-cholesterol and reducing atherosclerotic plaque size in animal models (32). However, long-term treatment with miR-33 inhibitors or genetic loss of miR-33 has been shown to result in detrimental unintended effects (33)(34)(35). As such, new strategies to deliver inhibitors to atherosclerotic plaques or disrupt binding of specific miR-33 targets could provide a more effective strategy.…”