Ubiquitin Ligase Wwp1 Gene Deletion Attenuates Diastolic Dysfunction in Pressure Overload Hypertrophy

<strong><em>Background.</em></strong> 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<em> Wwp1</em> would alter the progression of LVPO induced HFpEF. <strong><em>Methods/Results</em></strong><em>.</em> LV echocardiography in mice with global <em>Wwp1</em> deletion (n=41; <em>Wwp1^-/-</em>) 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 (<em>Wwp1^+/+</em>; 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 <em>Wwp1^-/-</em> mice. With LVPO, the E/A ratio, an index of LV filling, was 3.97 + 0.46 in <em>Wwp1^+/+</em> but was 1.73 + 0.19 in the <em>Wwp1^-/-</em> group (p&lt;0.05). At the transcriptional level, mRNA for fibrillar collagens (types I and III) decreased by approximately 50% in <em>Wwp1^-/-</em> compared to the <em>Wwp1^+/+</em> group at 4 weeks post-LVPO (p&lt;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 <em>Wwp1^-/-</em> group. <strong><em>Summary.</em></strong> The absence of <em>Wwp1</em> 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.<em>研究背景</em>。左心室射血分数保留型心力衰竭（Heart failure with a preserved left ventricular ejection fraction, HFpEF）多由长期左心室压力负荷过载（left ventricular pressure overload, LVPO）引发，并伴随细胞外基质（extracellular matrix, ECM）异常沉积。E3泛素连接酶WWP1是调控细胞外基质周转的核心因子。本研究验证如下假说：敲除Wwp1基因可改变左心室压力负荷过载诱导的HFpEF进展进程。<em>研究方法与结果</em>。对全局敲除Wwp1的小鼠（n=41；Wwp1^-/-）于12周龄时（基线期），以及左心室压力负荷过载建模（主动脉弓缩窄术，transverse aortic banding）或假手术（仅行开胸操作，不诱导压力负荷过载）后2周、4周开展左心室超声心动图检测。同月龄野生型小鼠（Wwp1^+/+；n=33）接受完全一致的实验流程。两组小鼠的左心室射血分数在压力负荷过载后均无显著变化，但左心室质量均出现升高，且Wwp1^-/-小鼠的左心室质量显著低于Wwp1^+/+组。伴随左心室压力负荷过载，反映左心室充盈功能的E/A比值在Wwp1^+/+组为3.97±0.46，而在Wwp1^-/-组仅为1.73±0.19（p<0.05）。转录水平分析显示，左心室压力负荷过载术后4周，Wwp1^-/-小鼠的Ⅰ型、Ⅲ型纤维胶原型mRNA表达水平较Wwp1^+/+组下降约50%（p<0.05），该差异与组织化学检测得到的左心室纤维胶原含量差异相符。此外，促进细胞外基质沉积的调控因子（如转化生长因子，transforming growth factor, TGF）的mRNA水平在左心室压力负荷过载后升高，但Wwp1^-/-组的该升高幅度显著降低。<em>研究总结</em>。敲除Wwp1基因可减轻左心室肥厚（left ventricular hypertrophy, LVH）的发生，并延缓HFpEF的后续进展。调控WWP1信号通路有望成为干预HFpEF自然病程的治疗靶点。