Cardiac specific increase in aldosterone production induces coronary dysfunction in aldosterone synthase-transgenic mice
Cardiac specific increase in aldosterone production induces coronary dysfunction in aldosterone synthase-transgenic mice
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DOI：
10.1161/01.cir.0000142858.44680.27
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发表时间：
2004-09-28
期刊：
影响因子：
37.8
通讯作者：
Delcayre, C
中科院分区：
文献类型：
--
作者：
Garnier, A;Bendall, JK;Delcayre, C
背景-循环醛固酮水平升高与心血管功能受损相关。虽然其机制尚未完全清楚，但醛固酮拮抗剂可降低心力衰竭和心肌梗死的总死亡率和心血管死亡率。醛固酮在实验模型中诱导心脏纤维化，其在大鼠心脏局部合成。这些观察表明，醛固酮在心脏的病理影响，仍然不清楚。方法和结果-转基因小鼠（TG），过表达的末端酶的醛固酮生物合成，醛固酮合成酶（AS），在心脏中已提出了基因靶向与α-肌球蛋白重链启动子。与野生型相比，雄性TG小鼠心脏中AS mRNA增加了100倍，醛固酮浓度增加了1.7倍。由于TG中心室/体重、AT（1）和AT（2）受体结合以及胶原含量未发生变化，因此未发现结构或心肌改变。超声心动图、离体心脏灌注或全细胞膜片钳实验均未发现心功能改变。相反，在离体灌注心脏中，冠状动脉功能受损，因为基础冠状动脉流量减少（基线值的约55%），并且与野生型相比，TG小鼠中对乙酰胆碱、缓激肽和硝普钠的血管舒张分别降低了75%、60%和75%，结论：雄性小鼠心脏醛固酮生成增加诱导了一个主要的冠状动脉内皮细胞，独立的功能障碍，心脏结构和功能没有可检测到的改变。然而，冠状动脉功能障碍可能对冠状动脉适应增加的流量需求是有害的。
Background-Elevated circulating aldosterone level is associated with impaired cardiovascular function. Although the mechanisms are not fully understood, aldosterone antagonists decrease total and cardiovascular mortality in heart failure and myocardial infarction. Aldosterone induces cardiac fibrosis in experimental models, and it is synthesized locally in rat heart. These observations suggest pathological effects of aldosterone in heart that remain unclear.Methods and Results-Transgenic mice (TG) that overexpress the terminal enzyme of aldosterone biosynthesis, aldosterone synthase (AS), in heart have been raised by gene targeting with the alpha-myosin heavy chain promoter. AS mRNA increased 100-fold and aldosterone concentration 1.7-fold in hearts of male TG mice relative to wild-type. No structural or myocardial alterations were evidenced, because ventricle/body weight, AT(1) and AT(2) receptor binding, and collagen content were unchanged in TG. No alteration in cardiac function was evidenced by echocardiography, isolated perfused heart, or whole-cell patch clamp experiments. In contrast, coronary function was impaired, because basal coronary flow was decreased in isolated perfused heart (-55% of baseline values), and vasodilatation to acetylcholine, bradykinin, and sodium nitroprusside was decreased by 75%, 60%, and 75%, respectively, in TG mice compared with wild-type, showing that the defect was not related to NO production.Conclusions-Increased cardiac aldosterone production in male mice induces a major coronary endothelium-independent dysfunction with no detectable alterations in cardiac structure and function. However, coronary dysfunction may be harmful for coronary adaptation to increased flow demand.