NADPH oxidase inhibition ameliorates cardiac dysfunction in rabbits with heart failure
NADPH oxidase inhibition ameliorates cardiac dysfunction in rabbits with heart failure
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NADPH 氧化酶抑制可改善心力衰竭兔的心功能障碍
DOI：
10.1007/s11010-010-0508-4
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发表时间：
2010-10-01
影响因子：
4.3
通讯作者：
Huang, Congxin
中科院分区：
文献类型：
--
作者：
Liu, Yu;Huang, He;Huang, Congxin
在实验性和临床HF中均发现NADPH氧化酶活性增加。本研究旨在探讨NADPH氧化酶抑制剂对心力衰竭兔心功能的影响及其机制。HF由容量和压力超负荷联合引起。将HF或假手术的家兔随机口服给予apocynin，NADPH氧化酶抑制剂（15 mg/d）或安慰剂8周。用超声心动图检测兔心功能和结构。用masson三色染色评价心肌纤维化。实时荧光定量PCR检测转化生长因子-β（TGF-β）、结缔组织生长因子（CTGF）、基质金属蛋白酶-2（MMP-2）和基质金属蛋白酶-9（MMP-9）的表达。逆转录-聚合酶链反应和Western Blot检测SERCA 2a和受磷蛋白（PLB）的表达。通过测量从ATP水解释放的Pi来评价SERCA 2a活性。HF兔表现为心功能不全和纤维化。这些变化与心肌NADPH氧化酶活性和氧化应激显著增加有关。与假手术组比较，HF组TGF-β、CTGF、MMP-2、MMP-9 mRNA表达明显升高，SERCA 2a、PLB表达明显降低，SERCA 2a活性降低。夹竹桃麻素可降低NADPH氧化酶活性和氧化应激，降低TGF-β、CTGF、MMP-2和MMP-9表达，减轻心脏纤维化，增加SERCA 2a和PLB表达，恢复SERCA 2a活性，从而改善心功能障碍。因此，慢性NADPH氧化酶抑制通过减少心脏纤维化和保留SERCA 2a表达和活性来改善心功能障碍。
Increased NADPH oxidase activity is found in both experimental and clinical HF. Here, we investigated the effects and mechanisms of NADPH oxidase inhibition on cardiac function in rabbits with HF. HF was induced by combined volume and pressure overload. Rabbits with HF or sham operation were randomized to orally receive apocynin, an inhibitor of NADPH oxidase (15 mg per day) or placebo for 8 weeks. Echocardiography was performed to examine the cardiac function and structure of the rabbits. Cardiac fibrosis was evaluated by masson’s trichrome staining. The transforming growth factor-beta (TGF-β), connective tissue growth factor (CTGF), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9) expression were measured by real-time PCR. The expression of SERCA2a and phospholamban (PLB) was detected by reverse transcription-polymerase chain reaction and Western Blot. SERCA2a activity was evaluated by measuring the Pi liberated from ATP hydrolysis. Rabbits with HF exhibited cardiac dysfunction and fibrosis. These changes were associated with significant increases in myocardial NADPH oxidase activity and oxidative stress. Compared with sham-operated rabbits, the TGF-β, CTGF, MMP-2, and MMP-9 mRNA expression significantly increased, the expression of SERCA2a and PLB dramatically decreased, and the SERCA2a activity was lower in HF rabbits. Apocynin reduced NADPH oxidase activity and oxidative stress, decreased TGF-β, CTGF, MMP-2, and MMP-9 expression, attenuated cardiac fibrosis, increased SERCA2a and PLB expression, restored SERCA2a activity, and thereby ameliorated cardiac dysfunction. Thus, chronic NADPH oxidase inhibition ameliorated cardiac dysfunction by decreasing cardiac fibrosis and preserving SERCA2a expression and activity.