Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment.
Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment.
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DOI：
10.1038/ncomms13710
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发表时间：
2016-12-14
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
间质纤维化在心力衰竭的发生发展中起着关键作用。在这里，我们展示了一种使胶原交联的酶--赖氨酰氧化酶样2(LOXL2)--对于病理性应激心脏的间质纤维化和机械功能障碍是必不可少的。在小鼠中，心脏应激激活成纤维细胞表达和分泌LOXL2到间质，引发应激心脏的纤维化、收缩和舒张期功能障碍。抗体介导的LOXL2抑制或基因破坏极大地减少了应激诱导的心脏纤维化和心腔扩张，改善了收缩和舒缩功能。LOXL2通过PI3K/AKT刺激心脏成纤维细胞产生转化生长因子-β-2，促进成纤维细胞向肌成纤维细胞的转化；LOXL2还作用于转化生长因子-β-2的下游，刺激肌成纤维细胞迁移。在患病的人心脏中，LOXL2在心脏间质中表达上调；其水平与胶原交联和心功能障碍有关。心力衰竭患者血清中LOXL2水平也升高，与其他心力衰竭生物标志物相关，提示人心力衰竭可能存在一种保守的机制。赖氨酰类氧化酶2(LOXL2)是一种促进细胞外基质蛋白支架形成的酶。在这里，作者表明LOXL2在压力超负荷诱导的心脏纤维化中起关键作用，并且在小鼠中通过抗体介导的抑制或基因破坏LOXL2显示出治疗心脏纤维化的潜力。
Interstitial fibrosis plays a key role in the development and progression of heart failure. Here, we show that an enzyme that crosslinks collagen—Lysyl oxidase-like 2 (Loxl2)—is essential for interstitial fibrosis and mechanical dysfunction of pathologically stressed hearts. In mice, cardiac stress activates fibroblasts to express and secrete Loxl2 into the interstitium, triggering fibrosis, systolic and diastolic dysfunction of stressed hearts. Antibody-mediated inhibition or genetic disruption of Loxl2 greatly reduces stress-induced cardiac fibrosis and chamber dilatation, improving systolic and diastolic functions. Loxl2 stimulates cardiac fibroblasts through PI3K/AKT to produce TGF-β2, promoting fibroblast-to-myofibroblast transformation; Loxl2 also acts downstream of TGF-β2 to stimulate myofibroblast migration. In diseased human hearts, LOXL2 is upregulated in cardiac interstitium; its levels correlate with collagen crosslinking and cardiac dysfunction. LOXL2 is also elevated in the serum of heart failure (HF) patients, correlating with other HF biomarkers, suggesting a conserved LOXL2-mediated mechanism of human HF. Lysyl oxidase-like 2 (LOXL2) is an enzyme that promotes scaffolding of extracellular matrix proteins. Here the authors show that LOXL2 is crucial for pressure-overload induced cardiac fibrosis, and that antibody-mediated inhibition or genetic disruption of Loxl2 in mice shows therapeutic potential for treatment of cardiac fibrosis.
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影响因子：
20.1
作者：
Dobaczewski M;Bujak M;Li N;Gonzalez-Quesada C;Mendoza LH;Wang XF;Frangogiannis NG
通讯作者：
Frangogiannis NG
影响因子：
37.8
作者：
Go AS;Mozaffarian D;Roger VL;Benjamin EJ;Berry JD;Blaha MJ;Dai S;Ford ES;Fox CS;Franco S;Fullerton HJ;Gillespie C;Hailpern SM;Heit JA;Howard VJ;Huffman MD;Judd SE;Kissela BM;Kittner SJ;Lackland DT;Lichtman JH;Lisabeth LD;Mackey RH;Magid DJ;Marcus GM;Marelli A;Matchar DB;McGuire DK;Mohler ER 3rd;Moy CS;Mussolino ME;Neumar RW;Nichol G;Pandey DK;Paynter NP;Reeves MJ;Sorlie PD;Stein J;Towfighi A;Turan TN;Virani SS;Wong ND;Woo D;Turner MB;American Heart Association Statistics Committee and Stroke Statistics Subcommittee
通讯作者：
American Heart Association Statistics Committee and Stroke Statistics Subcommittee
影响因子：
8.3
作者：
Lopez, Begona;Querejeta, Ramon;Diez, Javier
通讯作者：
Diez, Javier
影响因子：
4.8
作者：
Atsawasuwan, Phimon;Mochida, Yoshiyuki;Yamauchi, Mitsuo
通讯作者：
Yamauchi, Mitsuo
影响因子：
--
作者：
Gandhi, Parul U;Testani, Jeffrey M;Ahmad, Tariq
通讯作者：
Ahmad, Tariq