Background: Low thyroid hormone (TH) function is recognized as a significant contributor in the pathogenesis after acute myocardial infarction (MI). Endothelial dysfunction contributes significantly to the poor prognosis of MI. We hypothesize that long-term treatment with low dose T3 improves endothelial function and cardiac contractile activity compared to beta blocker, the current recommended therapy for MI. Methods: Adult female Sprague-Dawley rats were subjected to left anterior descending coronary artery ligation (MI) or sham surgeries. Survivors were randomly assigned to vehicle (MI, n=11), T3 (MI+T3, n=11) and metoprolol (MI+Meto, n=11). Vehicle, T3 (5 ug/kg/day) and metoprolol (2 mg/kg/day) were supplied in drinking water ad libitum immediately following MI for 2 months. Heart function and LV hemodynamics were measured. Isolated thoracic aortic rings were used to test relaxation response to acetylcholine (ACh) in a wire myograph. The maximal effect elicited by ACh (E max ) and the sensitivity to ACh (pEC 50 ) were analyzed. One-way ANOVA with Bonferroni correction was used for multiple comparisons. Results: Serum concentration of free and total T3 were normal in all the experimental groups. T3 and metoprolol improved LV contractile function measured by fractional shortening (21.88±2.06 vs 17.88±1.23%, p<0.01, T3 vs MI; 21.12±3.88 vs 17.88±1.23%, p<0.05, Meto vs MI; 46.86±1.84% for sham) and LV +d p /d t (7307±1128 vs 5479±810 mmHg/s, p<0.01, T3 vs MI; 7022±695 vs 5479±810 mmHg/s, p<0.05; Meto vs MI; 9160±1881 mmHg/s for sham). Aortas from vehicle-treated group exhibited a marked impairment of endothelial-dependent relaxation measured by pEC 50 (6.65±0.22 vs 7.19±0.16, p<0.001, MI vs Sham), which was significantly improved in the T3 treated group (6.96±0.22 vs. 6.65±0.22, p<0.01, T3 vs MI) but not in metoprolol group (6.85±0.21 versus 6.65±0.22, p=0.22, Meto vs MI). T3 and metoprolol increased maximal relaxation measured by E max (90.56±3.55 vs 79.50±3.98%, p<0.001, T3 vs MI; 89.81±6.75% vs 79.50±3.98%, P<0.001, Meto vs MI; 96.93±1.91% for sham). Conclusion: Long-term treatment with a physiological dose of T3 following MI is equally effective as metoprolol on LV function while improving endothelial function as an additional benefit.
Obesity in the United States is associated with overconsumption of the high fat and high carbohydrate western diet. It is a major risk factor for hypertension. The mechanisms by which obesity contributes to the development of hypertension remain unresolved. While obese women are three-fold more likely to develop hypertension than lean women, the majority of obesity-induced hypertension research has been conducted using male cohorts. Thus, there is an urgent need to investigate the pathophysiology of obesity-induced hypertension in women. A previous study from our lab demonstrated that endothelial dysfunction found in obese female rats is associated with TLR4 signaling activation in the aorta revealing an inflammatory state in a conduit artery during obesity. The goal of this present study is to investigate whether weight loss by reversal of western diet-induced obesity normalizes TLR4 signaling in conduit and resistance arteries. To address this question, eight-week-old female Wistar rats were randomized into three experimental groups: the Obese group (n=10) was fed a western diet (21% fat, 50% carbohydrate [34% sucrose], 20% protein) and the Lean group (n=10) was fed a standard chow diet (5% fat, 48.7% carbohydrate [3.2% sucrose], 24.1% protein) for 20 weeks. The weight loss group (n=10) was fed a western diet for 20 weeks and a standard chow diet for 8 weeks. While weight loss reduced BMI (0.65 ±0.03 vs.0.82 ±0.02 obese, p<0.01), systolic blood pressure consistently measured at 7pm by tail-cuff plethysmography remained elevated (139.83 ± 15.3 vs.150.06 ± 4.5, p=0.09). At the experimental endpoint, thoracic aortas and mesenteric arteries were obtained for molecular analysis of TLR4 signaling. As previously shown, aortic TLR4 signaling of the obese group was activated. Weight loss normalized TLR4 and MyD88 expression in thoracic aortas; however, expression of MyD88 remained increased in mesenteric arteries (2.8 fold increase, p<0.01, n=6). This suggests that persistent hypertension despite weight loss is associated with a failure of TLR4-MyD88 signaling to normalize in the resistance vessels.
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