Dimethylthiourea normalizes velocity-dependent, but not force-dependent, index of ventricular performance in diabetic rats: role of myosin heavy chain isozyme.
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.
Yeih
Dong-Feng
DF
1Department of Cardiology, Far Eastern Memorial Hospital, Pan-Chiao, Taipei County, Taiwan, Republic of China.
Yeh
Hung-I
HI
Hsin
Ho-Tsung
HT
Lin
Lian-Yu
LY
Chiang
Fu-Tien
FT
Tseng
Chuen-Den
CD
Chu
Shu-Hsun
SH
Tseng
Yung-Zu
YZ
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002317:Cardiovascular Agents / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004548:Elasticity; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D017665:Hydroxyl Radical / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D020033:Protein Isoforms; D051381:Rats; D017208:Rats, Wistar; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control
D051792:Basic Helix-Loop-Helix Proteins; D002317:Cardiovascular Agents; D016166:Free Radical Scavengers; D017665:Hydroxyl Radical; D018006:Myogenic Regulatory Factors; D018995:Myosin Heavy Chains; D020033:Protein Isoforms; D013890:Thiourea; C097341:helix-loop-helix protein, eHAND; C038983:1,3-dimethylthiourea