Department of Cardiology, Charité Center 11, Charité-University Medicine Berlin, Hindenburgdamm 30, Berlin, Germany.
Institute of Pharmacology, Center of Drug Absorption and Transport, University Medicine Greifswald, Felix-Hausdorff-Str. 3, Greifswald, Germany.
Eur Heart J. 2019 Oct 21;40(40):3318-3332. doi: 10.1093/eurheartj/ehz117.
Heart failure with preserved ejection fraction (HFpEF) and pathological cardiac aging share a complex pathophysiology, including extracellular matrix remodelling (EMR). Protease-activated receptor 2 (PAR2) deficiency is associated with EMR. The roles of PAR1 and PAR2 have not been studied in HFpEF, age-dependent cardiac fibrosis, or diastolic dysfunction (DD).
Evaluation of endomyocardial biopsies from patients with HFpEF (n = 14) revealed that a reduced cardiac PAR2 expression was associated with aggravated DD and increased myocardial fibrosis (r = -0.7336, P = 0.0028). In line, 1-year-old PAR2-knockout (PAR2ko) mice suffered from DD with preserved systolic function, associated with an increased age-dependent α-smooth muscle actin expression, collagen deposition (1.7-fold increase, P = 0.0003), lysyl oxidase activity, collagen cross-linking (2.2-fold increase, P = 0.0008), endothelial activation, and inflammation. In the absence of PAR2, the receptor-regulating protein caveolin-1 was down-regulated, contributing to an augmented profibrotic PAR1 and transforming growth factor beta (TGF-β)-dependent signalling. This enhanced TGF-β/PAR1 signalling caused N-proteinase (ADAMTS3) and C-proteinase (BMP1)-related increased collagen I production from cardiac fibroblasts (CFs). PAR2 overexpression in PAR2ko CFs reversed these effects. The treatment with the PAR1 antagonist, vorapaxar, reduced cardiac fibrosis by 44% (P = 0.03) and reduced inflammation in a metabolic disease model (apolipoprotein E-ko mice). Patients with HFpEF with upstream PAR inhibition via FXa inhibitors (n = 40) also exhibited reduced circulating markers of fibrosis and DD compared with patients treated with vitamin K antagonists (n = 20).
Protease-activated receptor 2 is an important regulator of profibrotic PAR1 and TGF-β signalling in the heart. Modulation of the FXa/FIIa-PAR1/PAR2/TGF-β-axis might be a promising therapeutic approach to reduce HFpEF.
射血分数保留型心力衰竭（HFpEF）和病理性心脏老化具有复杂的病理生理学，包括细胞外基质重塑（EMR）。蛋白酶激活受体 2（PAR2）缺乏与 EMR 有关。PAR1 和 PAR2 的作用在 HFpEF、年龄依赖性心肌纤维化或舒张功能障碍（DD）中尚未得到研究。
评估 HFpEF 患者的心肌活检（n=14）显示，心脏 PAR2 表达减少与 DD 加重和心肌纤维化增加相关（r=-0.7336，P=0.0028）。与此一致，1 岁的 PAR2 敲除（PAR2ko）小鼠出现 DD 但保留收缩功能，伴有年龄依赖性α-平滑肌肌动蛋白表达增加、胶原沉积（增加 1.7 倍，P=0.0003）、赖氨酰氧化酶活性、胶原交联（增加 2.2 倍，P=0.0008）、内皮激活和炎症。在缺乏 PAR2 的情况下，受体调节蛋白 caveolin-1 下调，导致纤维母细胞中促纤维化 PAR1 和转化生长因子β（TGF-β）依赖性信号增强。这种增强的 TGF-β/PAR1 信号导致心脏成纤维细胞（CFs）中 N 蛋白酶（ADAMTS3）和 C 蛋白酶（BMP1）相关的胶原 I 产生增加。PAR2ko CFs 中的 PAR2 过表达逆转了这些作用。PAR1 拮抗剂 vorapaxar 的治疗使心脏纤维化减少 44%（P=0.03），并减少代谢疾病模型（载脂蛋白 E 敲除小鼠）中的炎症。与接受维生素 K 拮抗剂治疗的患者（n=20）相比，接受 FXa 抑制剂（n=40）上游 PAR 抑制的 HFpEF 患者也表现出循环纤维化和 DD 标志物减少。
蛋白酶激活受体 2 是心脏中促纤维化 PAR1 和 TGF-β 信号的重要调节剂。FXa/FIIa-PAR1/PAR2/TGF-β 轴的调节可能是减少 HFpEF 的一种有前途的治疗方法。
