Background. Heart failure with a preserved left ventricular (LV) ejection fraction (HFpEF) often arises from a prolonged LV pressure overload (LVPO) and accompanied by abnormal extracellular matrix (ECM) accumulation. The E3 ubiquitin ligase WWP1 is a fundamental determinant ECM turnover. We tested the hypothesis that genetic ablation of Wwp1 would alter the progression of LVPO induced HFpEF. Methods/Results. LV echocardiography in mice with global Wwp1 deletion (n=41; Wwp1^-/-) was performed at 12 weeks of age (Baseline) and then at 2 and 4 weeks following LVPO (transverse aortic banding) or surgery without LVPO induction. Age-matched wild type mice (Wwp1^+/+; n=33) underwent identical protocols. LV EF remained constant and unchanged with LVPO and LV mass increased in both groups but was lower in the Wwp1^-/- mice. With LVPO, the E/A ratio, an index of LV filling, was 3.97 + 0.46 in Wwp1^+/+ but was 1.73 + 0.19 in the Wwp1^-/- group (p<0.05). At the transcriptional level, mRNA for fibrillar collagens (types I and III) decreased by approximately 50% in Wwp1^-/- compared to the Wwp1^+/+ group at 4 weeks post-LVPO (p<0.05) and was paralleled by a similar difference in LV fibrillar collagen content as measured by histochemistry. Moreover, mRNA levels for determinants favoring ECM accumulation, such as transforming growth factor (TGF) increased with LVPO, but were lower in the Wwp1^-/- group. Summary. The absence of Wwp1 reduced the development of LVH and subsequent progression to HFpEF. Modulating the WWP1 pathway could be a therapeutic target to alter the natural history of HFpEF.

中文翻译：

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泛素连接酶 Wwp1 基因缺失减轻压力超负荷肥大的舒张功能障碍

背景。保留左心室 (LV) 射血分数 (HFpEF) 的心力衰竭通常由长期的 LV 压力超负荷 (LVPO) 引起，并伴有异常的细胞外基质 (ECM) 积聚。E3 泛素连接酶 WWP1 是 ECM 转换的基本决定因素。我们测试了 Wwp1 的基因消融会改变 LVPO 诱导的 HFpEF 进展的假设。方法/结果。在 12 周龄（基线），然后在 LVPO（横向主动脉束带）或没有 LVPO 诱导的手术后 2 周和 4 周，对具有整体 Wwp1 缺失（n=41；Wwp1 ^-/-）的小鼠进行 LV 超声心动图检查。年龄匹配的野生型小鼠 (Wwp1 ^+/+; n=33) 经历了相同的协议。LV EF 保持恒定不变，LVPO 和 LV 质量在两组中都增加，但在 Wwp1 ^-/-小鼠中较低。对于 LVPO，作为 LV 充盈指数的 E/A 比在 Wwp1 ^{+/+ 中}为 3.97 + 0.46，但在 Wwp1 ^-/-组中为 1.73 + 0.19 （p<0.05）。在转录水平上，与 Wwp1 ^+/+相比，Wwp1 ^{-/- 中}纤维状胶原蛋白（I 型和 III 型）的 mRNA 减少了约 50%LVPO 后 4 周（p < 0.05）组，并通过组织化学测量的 LV 纤维胶原含量的相似差异与之平行。此外，有利于 ECM 积累的决定因素的 mRNA 水平，例如转化生长因子 (TGF)，随着 LVPO 的增加而增加，但在 Wwp1 ^-/-组中较低。概括。Wwp1 的缺失减少了 LVH 的发展和随后向 HFpEF 的进展。调节 WWP1 通路可能是改变 HFpEF 自然病程的治疗靶点。