Gender disparity of streptozotocin-induced intrinsic contractile dysfunction in murine ventricular myocytes: Role of chronic activation of Akt
Gender disparity of streptozotocin-induced intrinsic contractile dysfunction in murine ventricular myocytes: Role of chronic activation of Akt
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DOI：
10.1111/j.1440-1681.2006.04331.x
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发表时间：
2006-01-01
影响因子：
2.9
通讯作者：
Ren, J
中科院分区：
文献类型：
--
作者：
Ceylan-Isik, AF;LaCour, KH;Ren, J
1.临床、流行病学和实验证据表明，在包括糖尿病性心肌病在内的心血管疾病的进展中，女性具有"优势“。推测这种“性别偏见”可能是由于性激素和内在心肌收缩特性的性别差异.本研究旨在研究糖尿病和性别对心脏收缩功能和心脏存活信号分子Akt激活的影响。用链脲佐菌素（STZ）在成年小鼠中诱导短期（2周）糖尿病。使用IonOptix MyoCam系统（IonOptix Corporation，米尔顿，MA，美国）评价分离的心室肌细胞的机械和细胞内Ca 2+特性。采用蛋白质印迹法检测总Akt和磷酸化Akt.与雄性小鼠相比，雌性小鼠心肌细胞显示出较小的峰值缩短（PS）幅度和最大缩短/恢复速度（dL/dt），PS时间和90%恢复时间较长。在雄性小鼠心肌细胞中，糖尿病显著降低PS、dL/dt、延长TR 90、延迟细胞内Ca 2+清除和减少肌浆网（SR）Ca 2+释放。所有这些异常，除了SR Ca 2+，释放被掩盖的女性。随着刺激频率的增加（从0.1到5.0 Hz）和蛋白质羰基损伤，PS的负阶梯在所有动物组之间是相当的.女性和糖尿病独立地增强Akt的磷酸化而不影响总Akt表达。有趣的是，STZ诱导的短期糖尿病未能引起女性心脏中Akt的额外磷酸化。总之，目前的数据显示，STZ诱导受损的心脏收缩功能和改变细胞内Ca 2+处理的男性，但不是女性，部分原因是内在的机械差异和Akt激活状态的性别。
1. Clinical, epidemiological and experimental evidence suggests a 'female advantage' in the progression of cardiovascular diseases, including diabetic cardiomyopathy. It is speculated that this 'gender bias' may be due to gender-related differences in sex hormones and intrinsic myocardial contractile properties.2. The present study was designed to examine the impact of diabetes and gender on cardiac contractile function and activation of the cardiac survival signalling molecule Akt. Short-term (2 weeks) diabetes was induced in adult mice of both genders with streptozotocin (STZ). Mechanical and intracellular Ca2+ properties of isolated ventricular myocytes were evaluated using an IonOptix MyoCam((R)) system (IonOptix Corporation, Milton, MA, USA). Total and phosphorylated Akt were evaluated using western blot analysis.3. Female mouse myocytes displayed smaller peak shortening (PS) amplitude and maximal velocity of shortening/relengthening (dL/dt), longer time to PS and time to 90% relengthening compared with male counterparts. Diabetes significantly reduced PS, dL/dt, prolonged TR90, delayed intracellular Ca2+ clearing and reduced sarcoplasmic reticulum (SR) Ca2+ release in male mouse myocytes. All these abnormalities, with the exception of SR Ca2+, release were masked by the female gender.4. The negative staircase of PS with increased stimulus frequency (from 0.1 to 5.0 Hz) and protein carbonyl damage were comparable among all animal groups.5. Female gender and diabetes independently enhanced phosphorylation of Akt without affecting total Akt expression. Interestingly, STZ-induced short-term diabetes failed to elicit additional phosphorylation of Akt in female hearts.6. In summary, the present data revealed that STZ induced impaired cardiac contractile function and altered intracellular Ca2+ handling in males, but not females, partially due to intrinsic mechanical differences and Akt activation status between genders.