Sildenafil ameliorates right ventricular early molecular derangement during left ventricular pressure overload.
Sildenafil ameliorates right ventricular early molecular derangement during left ventricular pressure overload.
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DOI：
10.1371/journal.pone.0195528
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Takimoto E
中科院分区：
文献类型：
--
作者：
Imai Y;Kariya T;Iwakiri M;Yamada Y;Takimoto E
左心衰竭后右室功能不全与预后不良有关。RV重构被认为是由于继发性肺动脉高压(PH)导致的RV后负荷增加到LV功能受损而引起的；然而，RV分子的改变可能发生在疾病的早期阶段。CGMP(CGMP)-磷酸二酯酶5(PDE5)抑制剂广泛用于肺血管舒张性肺高压的治疗，已显示出直接的心脏益处，但其对LV疾病的RV的影响尚不完全确定。我们的研究表明，在左心室压力超负荷期间，右室血流动力学没有改变时，右室分子的改变就会发生，而PDE5的抑制作用可以改善右室的分子改变。两天中度LV压力超负荷(横动脉收缩)对小鼠右室压力/功能和RV重量均无影响，但仅引起轻度LV肥厚。重要的是，RV游离壁心肌的病理分子特征已经被诱导，包括肥大和炎症的基因标志物上调，以及细胞外信号调节激酶(ERK)和钙调神经磷酸酶(Calcineurin)的激活。伴随而来的PDE5抑制(西地那非)阻止了这种病理基因的诱导，以及在RV和LV中ERK和钙调神经磷酸酶的激活。重要的是，地塞米松也可以防止这些RV分子变化，类似于西地那非治疗。这些结果提示炎症在RV和LV早期病理性室间相互作用中起重要作用。本研究首次证实了RV与LV之间存在新的早期分子串扰，先于LV疾病的RV血流动力学改变，并支持通过增强cGMP信号通路治疗心脏病的治疗策略。
Right ventricular (RV) dysfunction following left ventricular (LV) failure is associated with poor prognosis. RV remodeling is thought initiated by the increase in the afterload of RV due to secondary pulmonary hypertension (PH) to impaired LV function; however, RV molecular changes might occur in earlier stages of the disease. cGMP (cyclic guanosine monophosphate)-phosphodiesterase 5 (PDE5) inhibitors, widely used to treat PH through their pulmonary vasorelaxation properties, have shown direct cardiac benefits, but their impacts on the RV in LV diseases are not fully determined. Here we show that RV molecular alterations occur early in the absence of RV hemodynamic changes during LV pressure-overload and are ameliorated by PDE5 inhibition. Two-day moderate LV pressure-overload (transverse aortic constriction) neither altered RV pressure/ function nor RV weight in mice, while it induced only mild LV hypertrophy. Importantly, pathological molecular features were already induced in the RV free wall myocardium, including up-regulation of gene markers for hypertrophy and inflammation, and activation of extracellular signal-regulated kinase (ERK) and calcineurin. Concomitant PDE5 inhibition (sildenafil) prevented induction of such pathological genes and activation of ERK and calcineurin in the RV as well as in the LV. Importantly, dexamethasone also prevented these RV molecular changes, similarly to sildenafil treatment. These results suggest the contributory role of inflammation to the early pathological interventricular interaction between RV and LV. The current study provides the first evidence for the novel early molecular cross-talk between RV and LV, preceding RV hemodynamic changes in LV disease, and supports the therapeutic strategy of enhancing cGMP signaling pathway to treat heart diseases.
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DOI：
10.1038/nrm3495
发表时间：
2013-01
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
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对医疗统计信息的自由使用的易于使用的软件“ EZR”的调查。
影响因子：
4.8
作者：
Kanda Y
通讯作者：
Kanda Y
影响因子：
37.8
作者：
Mohammed SF;Hussain I;AbouEzzeddine OF;Takahama H;Kwon SH;Forfia P;Roger VL;Redfield MM
通讯作者：
Redfield MM
影响因子：
5.8
作者：
Fiore, Daniela;Gianfrilli, Daniele;Isidori, Andrea M.
通讯作者：
Isidori, Andrea M.
影响因子：
39.3
作者：
Melenovsky, Vojtech;Hwang, Seok-Jae;Borlaug, Barry A.
通讯作者：
Borlaug, Barry A.