Heart Failure Research Group, Baker IDI Heart and Diabetes Research Institute, Melbourne, Australia.
Circ Heart Fail. 2011 Sep;4(5):651-8. doi: 10.1161/CIRCHEARTFAILURE.110.960831. Epub 2011 Jun 17.
Extensive evidence implicates aldosterone excess in the development and progression of cardiovascular disease states including hypertension, metabolic syndrome, cardiac hypertrophy, heart failure, and cardiorenal fibrosis. Recent studies show that activation of inflammatory cascade may play a specific role in the sequelae of mineralocorticoid activation, although the linking mechanism remains unclear. We tested the possibility that secondary stimulation of the stromal-derived factor 1/CXC chemokine receptor 4 (SDF-1/CXCR4) pathway plays a contributory role.
We investigated the effect of the highly selective CXCR4 antagonist AMD3465 (6 mg/kg per day for 6 weeks through minipump) in dexoycorticosterone acetate (DOCA)-treated, uninephrectomized mice. CXCR4 antagonism significantly attenuated the induction of cardiac fibrosis, renal fibrosis, hypertension, and left ventricular hypertrophy by DOCA. Mineralocorticoid excess also stimulated the accumulation of T-lymphocytes in the heart and kidney and this was significantly blunted by CXCR4 inhibition.
Taken together, these data strongly implicate the SDF-1/CXCR4 axis in the pathogenesis of mineralocorticoid excess induced hypertension, inflammation, and cardiorenal fibrosis. This insight provides a new potential therapeutic approach for the treatment of specific aspects of mineralocorticoid mediated cardiovascular disease.
大量证据表明，醛固酮过多与心血管疾病状态的发生和进展有关，包括高血压、代谢综合征、心肌肥厚、心力衰竭和心肾纤维化。最近的研究表明，炎症级联的激活可能在盐皮质激素激活的后遗症中发挥特定作用，尽管其联系机制尚不清楚。我们测试了基质衍生因子 1/CXC 趋化因子受体 4（SDF-1/CXCR4）途径的二次刺激是否具有促进作用的可能性。
我们研究了高度选择性 CXCR4 拮抗剂 AMD3465（通过迷你泵每天 6 毫克/千克，持续 6 周）在醋酸脱氧皮质酮（DOCA）处理的单侧肾切除小鼠中的作用。CXCR4 拮抗作用显著减弱了 DOCA 诱导的心脏纤维化、肾脏纤维化、高血压和左心室肥厚。醛固酮过多还刺激心脏和肾脏中 T 淋巴细胞的积累，而这种积累在 CXCR4 抑制时明显减弱。
综上所述，这些数据强烈表明 SDF-1/CXCR4 轴在醛固酮过多引起的高血压、炎症和心肾纤维化发病机制中起作用。这一发现为治疗特定的盐皮质激素介导的心血管疾病提供了一种新的潜在治疗方法。
