Key result
miR-148a-3p inhibition enhances angiogenesis and improves post-MI cardiac performance in preclinical models.
Why the study?
Senescent endothelial cells compromise the angiogenic response and tissue regeneration following myocardial infarction. This study evaluated miR-148a-3p as a potential therapeutic target to mitigate endothelial senescence and promote post-MI vascular repair.
Does inhibition of miR-148a-3p improve endothelial function, attenuate senescence, and enhance cardiac performance in human endothelial cells and a murine model of acute myocardial infarction?
Does inhibition of miR-148a-3p improve endothelial function, attenuate senescence, and enhance cardiac performance in human endothelial cells and a murine model of acute myocardial infarction?
Preclinical evidence demonstrates that inhibiting miR-148a-3p reduces endothelial senescence, promotes angiogenesis in vitro, and improves cardiac function in mice following acute myocardial infarction.
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.
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Kalies et al. (2026) studied Myocardial infarction and endothelial senescence. miR-148a-3p inhibition was evaluated on Endothelial function (proliferation, migration, sprouting, tube formation), senescence markers, and in vivo cardiac performance (including global longitudinal strain) (p=<0.01). Inhibition of miR-148a-3p enhanced endothelial proliferation (p<0.01) and angiogenesis (p<0.05), reduced senescence (p<0.05), and improved post-MI cardiac performance in mice.
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