Abstract 1001: Short-term Treatment with DITPA, a Thyroid Hormone Analog, Improves Postischemic Coronary Flow and Cardiac Contractile Function in Hypertensive Endothelial Nitric Oxide Synthase Knockout (eNOS-KO) Mice
There is now growing evidence that acute or short-term treatment with thyroid hormone (TH) can improve postischemic cardiac function by direct, nongenomic effects. The effects of TH on cardiac contraction and relaxation are mainly mediated by increases in sarcoplasmic reticulum Ca2+-ATPase (SERCA) or decreases in phospholamban (PLB) levels. It is also reported that both genomic and nongenomic actions of TH could interface at SERCA2a, where gene expression is genomic and enzyme activity is nongenomic. TH also has acute direct effects independent of cAMP, cGMP, or NO. eNOS-KO mice are hypertensive with hypertrophied heart and suffer exaggerated postischemic cardiac dysfunction compared to WT mice. These mice have reduced SERCA2a enzyme activity and we also noted low cardiac SERCA2a expression. DITPA (3,5-diiodothyropropionic acid) is a TH analog with low metabolic activity, however, it is unknown whether DITPA treatment could improve postischemic myocardial function in hypertrophied eNOS-KO hearts. In vitro ischemia-reperfusion studies were performed in Langendorff hearts from WT and eNOS-KO mice after DITPA treatment (3.75 mg/kg/day, SC, 7 days), and the results were compared with untreated mice. In contrast to DITPA-treated WT mice (Table 1⇓), DITPA-treated eNOS-KO hearts had significantly improved postischemic coronary flow, LVDP, and LVEDP (Table 2⇓). Echocardiography revealed impaired cardiac contractile function in DITPA-treated WT mice. DITPA neither increased cardiac SERCA2a nor did it decrease PLB levels in Western blots. These findings suggest that DITPA can directly improve postischemic cardiac function in hypertrophied eNOS-KO hearts with less SERCA2a.