Background:Despite its established significance in fibrotic cardiac remodeling, clinical benefits of global inhibition of TGF (transforming growth factor)-β1 signaling remain controversial. LRG1 (leucine-rich-α2 glycoprotein 1) is known to regulate endothelial TGFβ signaling. This study evaluated the role of LRG1 in cardiac fibrosis and its transcriptional regulatory network in cardiac fibroblasts.Methods:Pressure overload–induced heart failure was established by transverse aortic constriction. Western blot, quantitative reverse transcription polymerase chain reaction, immunofluorescence, and immunohistochemistry were used to evaluate the expression level and pattern of interested targets or pathology during fibrotic cardiac remodeling. Cardiac function was assessed by pressure-volume loop analysis.Results:LRG1 expression was significantly suppressed in left ventricle of mice with transverse aortic constriction–induced fibrotic cardiac remodeling (mean difference, −0.00085 [95% CI, −0.0013 to −0.00043]; P=0.005) and of patients with end-stage ischemic-dilated cardiomyopathy (mean difference, 0.13 [95% CI, 0.012–0.25]; P=0.032). More profound cardiac fibrosis (mean difference, −0.014% [95% CI, −0.029% to −0.00012%]; P=0.048 for interstitial fibrosis; mean difference, −1.3 [95% CI, −2.5 to −0.2]; P=0.016 for perivascular fibrosis), worse cardiac dysfunction (mean difference, −2.5 ms [95% CI, −4.5 to −0.4 ms]; P=0.016 for Tau-g; mean difference, 13% [95% CI, 2%–24%]; P=0.016 for ejection fraction), and hyperactive TGFβ signaling in transverse aortic constriction–operated Lrg1-deficient mice (mean difference, −0.27 [95% CI, −0.47 to −0.07]; P<0.001), which could be reversed by cardiac-specific Lrg1 delivery mediated by adeno-associated virus 9. Mechanistically, LRG1 inhibits cardiac fibroblast activation by competing with TGFβ1 for receptor binding, while PPAR (peroxisome proliferator-activated receptor)-β/δ and TGFβ1 collaboratively regulate LRG1 expression via SMRT (silencing mediator for retinoid and thyroid hormone receptor). We further demonstrated functional interactions between LRG1 and PPARβ/δ in cardiac fibroblast activation.Conclusions:Our results established a highly complex molecular network involving LRG1, TGFβ1, PPARβ/δ, and SMRT in regulating cardiac fibroblast activation and cardiac fibrosis. Targeting LRG1 or PPARβ/δ represents a promising strategy to control pathological cardiac remodeling in response to chronic pressure overload.

中文翻译：

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TGF-β1和PPAR-β/δ对LRG1的协同调节可调节慢性压力超负荷引起的心脏纤维化。

背景：尽管在纤维化心脏重塑中具有确定的意义，但全面抑制TGF（转化生长因子）-β1信号传导的临床益处仍存在争议。已知LRG1（富含亮氨酸的α2糖蛋白1）调节内皮TGFβ信号传导。这项研究评估了LRG1在心脏纤维化中的作用及其在心脏成纤维细胞中的转录调控网络。方法：通过横向主动脉缩窄建立压力超负荷引起的心力衰竭。免疫印迹，定量逆转录聚合酶链反应，免疫荧光和免疫组化被用来评估纤维化心脏重塑过程中感兴趣的靶标或病理学的表达水平和模式。通过压力容量环分析评估心脏功能。结果：P = 0.005）和患有晚期缺血性扩张型心肌病的患者（平均差异为0.13 [95％CI，0.012-0.25]；P = 0.032）。较严重的心脏纤维化（平均差异为-0.014％[95％CI，-0.029％至-0.00012％]；间质纤维化的P = 0.048；平均差异为-1.3 [95％CI，-2.5至-0.2]；P对于血管周围纤维化= 0.016），心脏功能障碍加重（平均差异-2.5 ms [95％CI，-4.5至-0.4 ms]; P = 0.016对于Tau-g;平均差异13％[95％CI，2％ –24％]；P = 0.016（射血分数），以及在主动脉狭窄操作的Lrg1缺陷小鼠中表现出高活性的TGFβ信号（均值差，-0.27 [95％CI，-0.47至-0.07]；P<0.001），这可以通过腺相关病毒9介导的心脏特异性Lrg1传递来逆转。在机制上，LRG1通过与TGFβ1竞争受体结合而抑制心脏成纤维细胞活化，而PPAR（过氧化物酶体增殖物激活受体）-β/δ和TGFβ1共同调控LRG1通过SMRT（类视黄醇和甲状腺激素受体的沉默介体）表达。我们进一步证明了LRG1和PPARβ/δ在心脏成纤维细胞激活中的功能相互作用。结论：我们的结果建立了一个高度复杂的分子网络，涉及LRG1，TGFβ1，PPARβ/δ和SMRT来调节心脏成纤维细胞的激活和心脏纤维化。靶向LRG1或PPARβ/δ代表了一种有前途的策略，可响应慢性压力超负荷来控制病理性心脏重塑。