Inhibition of miR-148a reduces the progression of atherosclerosis in a “humanized” mouse model. This is the main conclusion reached by a recent investigation led by CIBERDEM by Dr. Noemi Rotllan, researcher of the Physiopathology of Lipid-Related Diseases Group of the Research Institute of the Hospital de la Santa Creu i Sant Pau – IIB Sant Pau that has just been published in Biomedicine & Pharmacotherapy.
Started at Yale University and completed at the IIB-Sant Pau, “this work has confirmed that anti-miR-148a therapy reduces both the size of the atherosclerotic plaque and vascular inflammation in a “humanized” mouse model such as the APOBTG Apobec-/- Ldlr+/.- mouse”, explains the researcher.
Dr. Rotllan also points out that “the antiatherogenic effect observed is mediated by the anti-inflammatory effects observed in macrophages treated with said therapy and independent of changes in the concentration of LDL and HDL cholesterol”.
miRNAs are molecules capable of regulating the expression of multiple genes involved in multifactorial pathologies such as atherosclerosis, and the use of therapies directed towards these miRNAs is widespread.
The importance of miR-148 in the regulation of lipid metabolism in macrophages, in cholesterol homeostasis and in inflammation was already known, but until now no study had been carried out on the contribution of miR-148a in the progression of the disease. atherosclerosis.
Specifically, prolonged inhibition with LNA 148a resulted in smaller plaques with reduced macrophage content but no change in vascular smooth cell content, and also decreased neutral lipid content in the aortic arch. Furthermore, such plaques were more stable as they had a thicker fibrous cap and smaller necrotic nuclei.
The work also shows that the inhibition of miR-148a in primary murine macrophages increases the expression of anti-inflammatory genes such as Arg1, Retlna and Mrc1, and decreases the expression of proinflammatory markers such as Nos2, Il6, Cox2 and Tnfa.
Thus, the inhibition of miR-148a decreases the inflammatory response of macrophages, polarizing them towards a phenotype known as M2 or antiatherogenic. In addition, they observed a decrease in cholesterol efflux using ApoA1 as acceptor in peritoneal macrophages treated with miR-148a. However, no significant changes in LDL or HDL cholesterol concentration were observed, as described above, although this is probably due to the use of a different mouse model and prolonged therapeutic treatment.
Taken together, these findings highlight the therapeutic potential of miR-148 inhibition to attenuate atherosclerosis progression and promote plaque stabilization, although more experiments with this type of molecule are still required for their possible application in this field.
Reference article
Noemi Rotllan, Xinbo Zhang, Alberto Canfráan-Duque, Leigh Goedeke, Raquel Griñán, Cristina M. Ramírez, Yajaira Suárez, Carlos Fernández-Hernando. “Antagonism of miR-148a attenuates atherosclerosis progression in APOBTGApobec-/-Ldlr+/- mice: A brief report” Biomedicine & Pharmacotherapy, Volume XX https://doi.org/10.1016/j.biopha.2022.113419
