Yeih Dong-Feng, Yeh Hung-I, Hsin Ho-Tsung, Lin Lian-Yu, Chiang Fu-Tien, Tseng Chuen-Den, Chu Shu-Hsun, Tseng Yung-Zu
1Department of Cardiology, Far Eastern Memorial Hospital, Pan-Chiao, Taipei County, Taiwan, Republic of China.
Am J Physiol Heart Circ Physiol. 2009 Oct;297(4):H1411-20. doi: 10.1152/ajpheart.01269.2008. Epub 2009 Jul 24.
Hydroxyl radicals and hydrogen peroxide are involved in the pathogenesis of systolic dysfunction in diabetic rats, but the precise mechanisms and the effect of antioxidant therapy in diabetic subjects have not been elucidated. We aimed to evaluate the effects of dimethylthiourea (DMTU), a potent hydroxyl radical scavenger, on both force-dependent and velocity-dependent indexes of cardiac contractility in streptozotocin (STZ)-induced early and chronic diabetic rats. Seventy-two hours and 8 wk after STZ (55 mg/kg) injection, diabetic rats were randomized to either DMTU (50 mg x kg(-1) x day(-1) ip) or vehicle treatment for 6 and 12 wk, respectively. All rats were then subjected to invasive hemodynamic studies. Maximal systolic elastance (E(max)) and maximum theoretical flow (Q(max)) were assessed by curve-fitting techniques in terms of the elastance-resistance model. Both normalized E(max) (E(maxn)) and afterload-adjusted Q(max) (Q(maxad)) were depressed in diabetic rats, concomitant with altered myosin heavy chain (MHC) isoform composition and its upstream regulators, such as myocyte enhancer factor-2 (MEF-2) and heart autonomic nervous system and neural crest derivatives (HAND). In chronic diabetic rats, DMTU markedly attenuated the impairment in Q(maxad) and normalized the expression of MEF-2 and eHAND and MHC isoform composition but exerted an insignificant benefit on E(maxn). Regarding preventive treatment, DMTU significantly ameliorated both E(maxn) and Q(maxad) in early diabetic rats. In conclusion, our study shows that DMTU has disparate effects on Q(maxad) and E(maxn) in chronic diabetic rats. The advantage of DMTU in chronic diabetic rats might involve normalization of MEF-2 and eHAND, as well as reversal of MHC isoform switch.
羟自由基和过氧化氢参与糖尿病大鼠收缩功能障碍的发病机制，但确切机制以及抗氧化治疗对糖尿病患者的影响尚未阐明。我们旨在评估强效羟自由基清除剂二甲基硫脲（DMTU）对链脲佐菌素（STZ）诱导的早期和慢性糖尿病大鼠心脏收缩力的力依赖性和速度依赖性指标的影响。在注射STZ（55 mg/kg）后72小时和8周，将糖尿病大鼠随机分为DMTU组（50 mg·kg⁻¹·d⁻¹，腹腔注射）或溶剂对照组，分别治疗6周和12周。然后对所有大鼠进行有创血流动力学研究。根据弹性-阻力模型，采用曲线拟合技术评估最大收缩弹性（E(max)）和最大理论流量（Q(max)）。糖尿病大鼠的标准化E(max)（E(maxn)）和后负荷调整后的Q(max)（Q(maxad)）均降低，同时肌球蛋白重链（MHC）异构体组成及其上游调节因子如肌细胞增强因子-2（MEF-2）、心脏自主神经系统和神经嵴衍生蛋白（HAND）发生改变。在慢性糖尿病大鼠中，DMTU显著减轻了Q(maxad)的损伤，并使MEF-2和eHAND的表达以及MHC异构体组成正常化，但对E(maxn)的改善作用不显著。对于预防性治疗，DMTU显著改善了早期糖尿病大鼠的E(maxn)和Q(maxad)。总之，我们的研究表明，DMTU对慢性糖尿病大鼠的Q(maxad)和E(maxn)有不同的影响。DMTU在慢性糖尿病大鼠中的优势可能涉及MEF-2和eHAND的正常化以及MHC异构体转换的逆转。
