Kawaguchi, SatoshiMoukette, BrunoSepúlveda, Marisa N.Hayasaka, TaikiAonuma, TatsuyaHaskell, Angela K.Mah, JessicaLiangpunsakul, SuthatTang, YaoliangConway, Simon J.Kim, Il-man2024-02-132024-02-132023-07-19Kawaguchi S, Moukette B, Sepúlveda MN, et al. SPRR1A is a key downstream effector of MiR-150 during both maladaptive cardiac remodeling in mice and human cardiac fibroblast activation. Cell Death Dis. 2023;14(7):446. Published 2023 Jul 19. doi:10.1038/s41419-023-05982-yhttps://hdl.handle.net/1805/38457MicroRNA-150 (miR-150) is conserved between rodents and humans, is significantly downregulated during heart failure (HF), and correlates with patient outcomes. We previously reported that miR-150 is protective during myocardial infarction (MI) in part by decreasing cardiomyocyte (CM) apoptosis and that proapoptotic small proline-rich protein 1a (Sprr1a) is a direct CM target of miR-150. We also showed that Sprr1a knockdown in mice improves cardiac dysfunction and fibrosis post-MI and that Sprr1a is upregulated in pathological mouse cardiac fibroblasts (CFs) from ischemic myocardium. However, the direct functional relationship between miR-150 and SPRR1A during both post-MI remodeling in mice and human CF (HCF) activation was not established. Here, using a novel miR-150 knockout;Sprr1a-hypomorphic (Sprr1ahypo/hypo) mouse model, we demonstrate that Sprr1a knockdown blunts adverse post-MI effects caused by miR-150 loss. Moreover, HCF studies reveal that SPRR1A is upregulated in hypoxia/reoxygenation-treated HCFs and is downregulated in HCFs exposed to the cardioprotective β-blocker carvedilol, which is inversely associated with miR-150 expression. Significantly, we show that the protective roles of miR-150 in HCFs are directly mediated by functional repression of profibrotic SPRR1A. These findings delineate a pivotal functional interaction between miR-150 and SPRR1A as a novel regulatory mechanism pertinent to CF activation and ischemic HF.en-USAttribution 4.0 InternationalMicroRNAsVentricular remodelingMyocardial infarctionFibroblastsArticle