Stumpf Christian, Petzi Sebastian, Seybold Katrin, Wasmeier Gerald, Arnold Martin, Raaz Dorette, Yilmaz Atilla, Daniel Werner G, Garlichs Christoph D
Department of Cardiology, University of Erlangen-Nuremberg, Ulmenweg 18, 91054 Erlangen, Germany.
Clin Sci (Lond). 2009 Jan;116(1):45-52. doi: 10.1042/CS20080042.
LV (left ventricular) remodelling is the basic mechanism of HF (heart failure) following MI (myocardial infarction). Although there is evidence that pro-inflammatory cytokines [including TNF-alpha (tumour necrosis factor-alpha) and IL-6 (interleukin-6)] are involved in the remodelling process, only little is known about the role of anti-inflammatory cytokines, such as IL-10. As accumulating evidence has revealed that statins possess anti-inflammatory properties, the aim of the present study was to elucidate the effect of atorvastatin on the modulation of the anti-inflammatory cytokine IL-10 and its effect on LV function in rats with HF subsequent to MI. Rats with MI, induced by permanent LAD (left anterior descending) branch coronary artery ligation, were treated for 4 weeks with atorvastatin (10 mg x kg(-1) of body weight x day(-1) via oral gavage) starting on the first day after induction of MI. Cardiac function was assessed by echocardiography and cardiac catheterization 4 weeks after MI induction. Membrane-bound and soluble fractions of TNF-alpha, IL-6 and IL-10 protein, the TNF-alpha/IL-10 ratio, serum levels of MCP-1 (monocyte chemoattractant protein-1) as well as myocardial macrophage infiltration were analysed. Treatment with atorvastatin significantly improved post-MI LV function (fractional shortening, +120%; dP/dt(max), +147%; and LV end-diastolic pressure, -27%). Furthermore atorvastatin treatment markedly decreased the levels of TNF-alpha, IL-6 and MCP-1, reduced myocardial infiltration of macrophages and significantly increased myocardial and serum levels of the anti-inflammatory cytokine IL-10. Thus the balance between pro-inflammatory and anti-inflammatory cytokines was shifted in the anti-inflammatory direction, as shown by a significantly decreased TNF-alpha/IL-10 ratio. Atorvastatin ameliorated early LV remodelling and improved LV function in rats with HF subsequent to MI. Our study suggests that the modulation of the balance between pro- and anti-inflammatory cytokines towards the anti-inflammatory cytokine IL-10 is one salutary mechanism underlying how atorvastatin influences post-MI remodelling and thus improves LV function.
左心室重构是心肌梗死后心力衰竭的基本机制。尽管有证据表明促炎细胞因子[包括肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）]参与了重构过程，但对于抗炎细胞因子如IL-10的作用却知之甚少。由于越来越多的证据表明他汀类药物具有抗炎特性，本研究的目的是阐明阿托伐他汀对抗炎细胞因子IL-10的调节作用及其对心肌梗死后心力衰竭大鼠左心室功能的影响。通过永久性结扎左冠状动脉前降支诱导心肌梗死的大鼠，在心肌梗死诱导后的第一天开始，用阿托伐他汀（10mg·kg⁻¹体重·天⁻¹，经口灌胃）治疗4周。在心肌梗死诱导4周后，通过超声心动图和心导管检查评估心脏功能。分析了TNF-α、IL-6和IL-10蛋白的膜结合和可溶性部分、TNF-α/IL-10比值、单核细胞趋化蛋白-1（MCP-1）的血清水平以及心肌巨噬细胞浸润情况。阿托伐他汀治疗显著改善了心肌梗死后的左心室功能（缩短分数，增加120%；dP/dt(max)，增加147%；左心室舒张末期压力，降低27%）。此外，阿托伐他汀治疗显著降低了TNF-α、IL-6和MCP-1的水平，减少了巨噬细胞的心肌浸润，并显著增加了抗炎细胞因子IL-10的心肌和血清水平。因此，促炎和抗炎细胞因子之间的平衡向抗炎方向转变，TNF-α/IL-10比值显著降低。阿托伐他汀改善了心肌梗死后心力衰竭大鼠的早期左心室重构并改善了左心室功能。我们的研究表明，将促炎和抗炎细胞因子之间的平衡调节为抗炎细胞因子IL-10是阿托伐他汀影响心肌梗死后重构并从而改善左心室功能的有益机制之一。
