Oxidative stress regulates left ventricular PDE5 expression in the failing heart.
Oxidative stress regulates left ventricular PDE5 expression in the failing heart.
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DOI：
10.1161/circulationaha.109.906818
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发表时间：
2010-04-06
期刊：
影响因子：
37.8
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Lu Z;Xu X;Hu X;Lee S;Traverse JH;Zhu G;Fassett J;Tao Y;Zhang P;dos Remedios C;Pritzker M;Hall JL;Garry DJ;Chen Y
PDE 5抑制已被证明在衰竭心脏中发挥深远的有益作用，表明PDE 5在充血性心力衰竭（CHF）的发展中发挥重要作用。本研究的目的是验证氧化应激导致心肌细胞中PDE 5表达增加以及PDE 5增加有助于CHF发展的假设。在来自终末期CHF患者和正常供体的左心室（LV）样品中以及来自横向主动脉缩窄（TAC）诱导的CHF后的小鼠的左心室（LV）样品中测定心肌PDE 5表达和细胞分布。与供体人心脏相比，CHF样品中心肌PDE 5蛋白增加约4.5倍，心肌PDE 5表达的增加与心肌氧化应激标志物3 '-硝基酪氨酸或4-羟基壬烯醛表达显著相关（p<0.05）。组织学检查显示，正常供心组织中PDE 5主要表达于血管平滑肌，而CHF供心组织中PDE 5表达增强。TAC诱导的CHF小鼠心肌PDE 5蛋白含量和活性也增加（p<0.05）。当给予SOD模拟物M40401来减轻氧化应激时，TAC引起的PDE 5蛋白和活性增加被减弱，心脏受到保护，免受LV肥大和CHF的影响。相反，增加心肌氧化应激在SOD 3基因敲除小鼠引起更大的增加PDE 5的表达和CHF后TAC。此外，给予西地那非抑制PDE 5可减弱TAC诱导的心肌氧化应激、PDE 5表达和CHF。心肌氧化应激增加衰竭心脏中PDE 5的表达通过用M40401处理减少氧化应激减弱心肌细胞PDE 5表达。这种和选择性抑制PDE 5保护心脏免受压力超负荷诱导的LV肥大和CHF。
PDE5 inhibition has been shown to exert profound beneficial effects in the failing heart, suggesting a significant role for PDE5 in the development of congestive heart failure (CHF). The purpose of this study is to test the hypothesis that oxidative stress causes increased PDE5 expression in cardiac myocytes and the increased PDE5 contributes to the development of CHF. Myocardial PDE5 expression and cellular distribution were determined in left ventricular (LV) samples from patients with end stage CHF and normal donors, and from mice after transverse aortic constriction (TAC)-induced CHF. Compared to donor human hearts, myocardial PDE5 protein was increased ~4.5 fold in CHF samples, and the increase of myocardial PDE5 expression was significantly correlated with myocardial oxidative stress markers 3’-nitrotyrosine or 4-hydroxynonenal expression (p<0.05). Histological examination demonstrated that PDE5 was mainly expressed in vascular smooth muscle in normal donor hearts, but its expression was increased in both cardiac myocytes and vascular smooth muscle of CHF hearts. Myocardial PDE5 protein content and activity also increased in mice after TAC-induced CHF (p<0.05). When the SOD mimetic M40401 was administered to attenuate oxidative stress, the increased PDE5 protein and activity caused by TAC was blunted, and the hearts were protected against LV hypertrophy and CHF. Conversely, increased myocardial oxidative stress in SOD3 KO mice caused a greater increase of PDE5 expression and CHF after TAC. In addition, administration of sildenafil to inhibit PDE5 attenuated TAC-induced myocardial oxidative stress, PDE5 expression and CHF. Myocardial oxidative stress increases PDE5 expression in the failing heart. Reducing oxidative stress by treatment with M40401 attenuated cardiomyocyte PDE5 expression. This and selective inhibition of PDE5 protected the heart against pressure overload induced LV hypertrophy and CHF.