Iwanaga Yoshitaka, Kihara Yasuki, Takenaka Hiroyuki, Kita Toru
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoinn-kawahara-cho Sakyo-ku, Kyoto 606-8507, Japan.
J Mol Cell Cardiol. 2006 Nov;41(5):798-806. doi: 10.1016/j.yjmcc.2006.07.004. Epub 2006 Aug 17.
Cardiac apelin has recently been suggested to contribute to the pathophysiology of heart failure (HF) in humans. In animal experiments, its infusion acutely improved systolic as well as diastolic LV function. Although its deficit could critically determine the cardiac dysfunction, its regulatory mechanism is unknown. Accordingly, we investigated the role and regulation of the cardiac apelin system in the diseased heart using Dahl salt-sensitive rats, which show a distinctive transition from compensatory LV hypertrophy (LVH) to HF. In the compensatory LVH stage, apelin and its receptor APJ mRNA showed no change compared with control animals, while these were markedly down-regulated in the HF stage (72% and 57% decrease, respectively). The rats were chronically treated with telmisartan (angiotensin type 1 receptor blocker [ARB], 5 mg/kg/day, n=9), ONO-4817 (matrix metalloproteinase [MMP] inhibitor, 200 mg/kg/day, n=9), bisoprolol (beta blocker, 3 mg/kg/day, n=6) or vehicle (0.5%CMC, n=9) from the LVH stage. Although the functional improvements were similar among the three treated groups 6 weeks after treatment, restoration of cardiac apelin and APJ expression was observed only in the ARB group. Furthermore, in angiotensin II-infused rats, cardiac apelin mRNA was decreased after 24 h of treatment and its restoration was achieved by treatment with ARB. These results indicate that the cardiac apelin system is markedly down-regulated in experimental HF and may be regulated by the angiotensin II-angiotensin type 1 receptor system directly. Inhibition of the renin-angiotensin system may have beneficial effects, at least in part, through restoration of the cardiac apelin system in the treatment of HF.
最近有研究表明，心脏中的apelin参与了人类心力衰竭（HF）的病理生理过程。在动物实验中，输注apelin可急性改善左心室（LV）的收缩和舒张功能。尽管apelin缺乏可能是心脏功能障碍的关键决定因素，但其调节机制尚不清楚。因此，我们使用Dahl盐敏感大鼠研究了患病心脏中apelin系统的作用和调节机制，该大鼠表现出从代偿性左心室肥厚（LVH）到HF的独特转变。在代偿性LVH阶段，与对照动物相比，apelin及其受体APJ的mRNA没有变化，而在HF阶段则显著下调（分别下降72%和57%）。从LVH阶段开始，对大鼠长期给予替米沙坦（血管紧张素1型受体阻滞剂[ARB]，5mg/kg/天，n=9）、ONO-4817（基质金属蛋白酶[MMP]抑制剂，200mg/kg/天，n=9）、比索洛尔（β受体阻滞剂，3mg/kg/天，n=6）或赋形剂（0.5%羧甲基纤维素，n=9）。尽管治疗6周后三个治疗组的功能改善相似，但仅在ARB组中观察到心脏apelin和APJ表达的恢复。此外，在输注血管紧张素II的大鼠中，治疗24小时后心脏apelin mRNA下降，而ARB治疗可使其恢复。这些结果表明，实验性HF中心脏apelin系统显著下调，可能直接受血管紧张素II-血管紧张素1型受体系统调节。抑制肾素-血管紧张素系统可能至少部分通过恢复心脏apelin系统对HF治疗产生有益作用。
