Inhibition of miR-148a-3p attenuates endothelial senescence and enhances angiogenesis after myocardial infarction

Abstract

A robust angiogenic response is essential for cardiac repair following myocardial infarction (MI); however, this process is compromised by senescent endothelial cells (ECs), which diminish angiogenic capacity and restrict tissue regeneration. MicroRNAs (miRNAs) represent a promising therapeutic avenue to enhance post-MI neovascularization. In this study, we evaluate miR-148a-3p as a potential therapeutic target to mitigate endothelial senescence and promote vascular repair, thereby contributing to innovative strategies for cardiovascular disease (CVD) treatment.

miR-148a-3p expression was quantified in human endothelial cells and murine tissues using qRT-PCR. The functional consequences of miR-148a-3p inhibition were examined in vitro, while therapeutic efficacy was assessed in vivo using a myocardial infarction model in young and aged C57BL/6J mice.

We observed a significant upregulation of miR-148a-3p in replicative senescent ECs (p < 0.01) and in aortic ECs from 24-month-old C57BL/6J mice. In both non-senescent and senescent HCAECs, inhibition of miR-148a-3p enhanced key endothelial functions, including proliferation (p < 0.01), migration (p < 0.05), sprouting (p < 0.05), and tube formation (p < 0.05). Moreover, miR-148a-3p knockdown reduced the expression of endothelial senescence markers (p < 0.01 to p < 0.05) and decreased SA-β-gal activity (p < 0.05) in both cellular states. Integrative in silico and experimental analyses identified several pro-angiogenic targets—NOGO-B (p < 0.05), AKT1 (p < 0.001), and HMOX-1 (p < 0.05)—as well as the anti-inflammatory gene NFKBIA (p < 0.01) as being upregulated in non-senescent ECs following miR-148a-3p inhibition. Concurrently, pro-senescent genes such as MAP2K1 and NRAS were significantly downregulated in replicative senescent ECs (p < 0.05).

Finally, systemic inhibition of miR-148a-3p was evaluated in a murine model of acute MI in young (3 months) and aged (20–22 months) C57BL/6J mice. Treatment improved clinical recovery parameters and enhanced cardiac performance, including global longitudinal strain, with particularly pronounced effects in aged animals.

In summary, miR-148a-3p inhibition improves endothelial function, attenuates senescence, and enhances cardiac regeneration in vivo, underscoring its therapeutic potential for combating age-related vascular dysfunction in CVD.