SPRR1A is a key downstream effector of MiR-150 during both maladaptive cardiac remodeling in mice and human cardiac fibroblast activation.
SPRR1A is a key downstream effector of MiR-150 during both maladaptive cardiac remodeling in mice and human cardiac fibroblast activation.
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DOI：
10.1038/s41419-023-05982-y
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发表时间：
2023-07-19
影响因子：
9
通讯作者：
Kim, Il-man
中科院分区：
文献类型：
--
作者：
Kawaguchi, Satoshi;Moukette, Bruno;Sepulveda, Marisa N.;Hayasaka, Taiki;Aonuma, Tatsuya;Haskell, Angela K.;Mah, Jessica;Liangpunsakul, Suthat;Tang, Yaoliang;Conway, Simon J.;Kim, Il-man
MicroRNA-150（miR-150）在啮齿动物和人类之间是保守的，在心力衰竭（HF）期间显着下调，并与患者结局相关。我们先前报道了miR-150在心肌梗死（MI）期间的保护作用部分是通过减少心肌细胞（CM）凋亡，并且促凋亡小脯氨酸丰富蛋白1a（Sprr 1a）是miR-150的直接CM靶点。我们还发现，Sprr 1a基因敲低小鼠心肌梗死后改善心功能障碍和纤维化，Sprr 1a在缺血心肌的病理性小鼠心脏成纤维细胞（CF）中上调。然而，miR-150和SPRR 1A在小鼠心肌梗死后重塑和人CF（HCF）激活过程中的直接功能关系尚未建立。在这里，使用一种新的miR-150敲除; Sprr 1a-亚型（Sprr 1ahypo/hypo）小鼠模型，我们证明了Sprr 1a敲除减弱了由miR-150丢失引起的MI后不良效应。此外，HCF研究表明，SPRR 1A在缺氧/再氧处理的HCF中上调，在暴露于心脏保护性β-阻滞剂卡维地洛的HCF中下调，这与miR-150表达呈负相关。值得注意的是，我们发现miR-150在HCF中的保护作用直接由促纤维化SPRR 1A的功能抑制介导。这些发现描述了miR-150和SPRR 1A之间的关键功能相互作用，作为与CF激活和缺血性HF相关的新的调节机制。
MicroRNA-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.
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DOI：
10.1161/circheartfailure.121.008686
发表时间：
2022-04
期刊：
Circulation. Heart failure
影响因子：
--
作者：
Aonuma T;Moukette B;Kawaguchi S;Barupala NP;Sepúlveda MN;Frick K;Tang Y;Guglin M;Raman SV;Cai C;Liangpunsakul S;Nakagawa S;Kim IM
通讯作者：
Kim IM
影响因子：
3.7
作者：
Liu Z;Zhou C;Liu Y;Wang S;Ye P;Miao X;Xia J
通讯作者：
Xia J
DOI：
10.1016/j.omtn.2017.06.005
发表时间：
2017-09-15
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
Chakraborty C;Sharma AR;Sharma G;Doss CGP;Lee SS
通讯作者：
Lee SS
影响因子：
--
作者：
Devaux, Yvan;Vausort, Melanie;Squire, Iain B.
通讯作者：
Squire, Iain B.
影响因子：
7
作者：
Moukette, Bruno;Kawaguchi, Satoshi;Sepulveda, Marisa N.;Hayasaka, Taiki;Aonuma, Tatsuya;Liangpunsakul, Suthat;Yang, Lei;Dharmakumar, Rohan;Conway, Simon J.;Kim, Il-man
通讯作者：
Kim, Il-man