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目的 探讨α-酮戊二酸（AKG）对模拟失重大鼠心功能与心脏重塑的影响及其可能的作用机制。方法 采用随机数字表法将SPF级健康雄性SD大鼠32只随机分为对照组、AKG组、模拟失重组、AKG+模拟失重组（各组8只），模拟失重组和AKG+模拟失重组采用尾部悬吊法建立模拟失重大鼠模型，AKG组和AKG+模拟失重组在造模前9周于饮水中加入2%AKG。28 d后检测各组大鼠体重、心脏重量、比目鱼肌湿重并计算比目鱼肌湿重与体重的比值；采用超声心动图测定左心室射血分数（EF）、左心室短轴缩短率（FS）、左心室舒张末期内径（LVIDd）、左心室收缩末期内径（LVIDs）、左心室前壁舒张期厚度（LVAWd）、左心室前壁收缩期厚度（LVAWs）；采用酶联免疫吸附试验测定各组心肌组织中腺苷三磷酸（ATP）、腺苷一磷酸（AMP）水平；采用HE染色与Masson染色观察各组心肌组织形态学及纤维化程度；实时荧光定量PCR检测各组心肌组织中心房钠尿肽（ANP）、脑钠肽（BNP）mRNA的表达；采用蛋白质印迹法检测各组心肌组织中黏着斑激酶（FAK）/Akt/叉头框蛋白O3A(FOXO3A)信号通路相关蛋白表达。结果 与对照组相比，模拟失重组大鼠体重、心脏重量、比目鱼肌湿重及比目鱼肌湿重/体重比值显著下降（均P<0.05）;EF、FS显著降低，LVIDd、LVIDs升高，LVAWd、LVAWs降低（均P<0.05）；心肌ATP含量显著减少，而AMP含量显著增加（均P<0.05）；心肌结构紊乱及胶原沉积增加；心肌组织中ANP、BNP mRNA表达显著上调（均P<0.05）；磷酸化黏着斑激酶（p-FAK）/FAK、磷酸化Akt(p-Akt)/Akt蛋白比值及FOXO3A蛋白表达则显著下调（均P<0.05）。AKG组心肌组织中p-FAK/FAK、p-Akt/Akt蛋白比值及FOXO3A蛋白表达较对照组显著上调（均P<0.05）,AKG组其余各项指标与对照组相比均无显著改变（均P>0.05）。与模拟失重组相比，AKG+模拟失重组上述改变明显改善，体重、心脏重量、比目鱼肌指标及比目鱼肌湿重/体重比值显著升高（均P<0.05）;EF、FS显著升高而LVIDd、LVIDs显著下降，LVAWd、LVAWs也显著回升（均P<0.05）;ATP含量显著增加，AMP含量显著减少（均P<0.05）；心肌结构较为整齐，纤维化区域明显减少；ANP、BNP mRNA表达显著下调（均P<0.05）;p-FAK/FAK、p-Akt/Akt蛋白比值及FOXO3A蛋白表达显著上调（均P<0.05）。结论 AKG干预能够改善模拟失重大鼠的心肌能量状态，减轻结构重构并恢复心功能，其机制可能与激活FAK/Akt/FOXO3A信号通路有关。
Abstract：Objective To investigate the effects of α-ketoglutarate(AKG) on cardiac function and cardiac remodeling in rats subjected to simulated microgravity and its potential mechanisms. Methods 32 SD rats were randomly divided into the control group, AKG group, simulated microgravity group, and AKG+simulated microgravity group using a random number table, with eight rats in each group. A simulated microgravity model was established in the simulated microgravity group and the AKG+simulated microgravity group using tail suspension, and AKG was administered via drinking water(2% concentration) for 28 days. After 28 days, body weight, heart weight and soleus muscle wet weight of the rats in each group were measured, and the ratio of soleus muscle wet weight to body weight was calculated. Echocardiography was used to measure left ventricular ejection fraction(EF), left ventricular fractional shortening(FS), left ventricular internal dimension at end diastole(LVIDd), left ventricular internal dimension at end-systole(LVIDs), left ventricular anterior wall diastolic thickness(LVAWd), and left ventricular anterior wall systolic thickness(LVAWs). ELISA was used to measure adenosine triphosphate(ATP) and adenylate monophosphate(AMP) levels in myocardial tissue. HE and Masson staining were used to observe myocardial tissue morphology and degree of fibrosis. Real-time PCR was used to detect the mRNA expression of atrial natriuretic peptide(ANP) and brain natriuretic peptide(BNP). Western blot was used to detect the expression of proteins related to the focal adhesion kinase/protein kinase B/forkhead box protein O3A(FAK/Akt/FOXO3A) signaling pathway in myocardial tissue. Results Compared with the control group, the body weight, heart weight, soleus muscle wet weight, and ration of soleus muscle wet weight to body weight in the simulated microgravity group were significantly decreased(all P<0.05). EF and FS were significantly decreased, while LVIDd and LVIDs were increased, and LVAWd and LVAWs were decreased(all P<0.05). Myocardial ATP content was significantly decreased, while AMP content was significantly increased(P<0.05). Myocardial structure was disordered and collagen deposition was increased. The mRNA expressions of ANP and BNP in myocardial tissue were significantly upregulated(all P<0.05). The protein ratios of p-FAK/FAK and p-Akt/Akt and FOXO3A protein expression were significantly downregulated(all P<0.05). The protein ratios of p-FAK/FAK, p-Akt/Akt and FOXO3A protein expression in myocardial tissue of the AKG group were significantly increased compared with the control group(P<0.05), the other indicators in the AKG group showed no significant changes compared with the control group(all P>0.05). Compared with the simulated microgravity group, the AKG+simulated microgravity group showed significant improvement on the above changes. Body weight, heart weight, soleus muscle wet weight, and ratio of soleus muscle wet weight to body weight in the AKG+simulated microgravity group increased significantly(all P<0.05). In the AKG+simulated microgravity group, EF and FS increased significantly, while LVIDd and LVIDs decreased significantly, and LVAWd and LVAWs also increased significantly(P<0.05); ATP content increased significantly, while AMP content decreased significantly(P<0.05). Myocardial structure became more regular, and the area of fibrosis was significantly reduced; ANP and BNP mRNA expressions were significantly downregulated(all P<0.05). p-FAK/FAK, p-Akt/Akt protein ratios, and FOXO3A protein expression were significantly upregulated(all P<0.05). Conclusion AKG intervention can improve myocardial energy status, alleviate structural remodeling, and restore cardiac function in simulated microgravity rats, its mechanism may be related to activation of the FAK/Akt/FOXO3A signaling pathway.
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基本信息:
DOI：10.16289/j.cnki.1002-0837.2026.01012
中图分类号:R852.22
引用信息:
[1]布尔列妮·吾力加别克,居勒德孜·海拉提,李永寿,等.模拟失重下AKG通过FAK/Akt/FOXO3A信号通路调节大鼠心功能及心脏重塑的机制研究[J].航天医学与医学工程,2026,37(01):65-71.DOI:10.16289/j.cnki.1002-0837.2026.01012.
基金信息:
国家自然科学基金地区科学基金项目（82460063）