Post-myocardial infarction exercise training beneficially regulates thyroid hormone receptor isoforms.

Thyroid hormone receptors (TRs) play a critical role in the expression of genes that are major determinants of myocardial contractility, including α-myosin heavy chain (α-MHC) and ß-MHC. After myocardial infarction (MI), changes in myocardial TRs consistently correlate with changes in thyroid hormone (TH) target gene transcription, and this is thought to play a key role in the progression to end-stage heart failure. Interestingly, post-MI exercise training has been shown to beneficially alter TH-target gene transcription and preserve cardiac function without changing serum TH. Therefore, in this study, we investigated whether mild exercise training alters expression of α1 and ß1 TR isoforms in post-MI rats. Seven-week-old male Sprague-Dawley rats underwent coronary ligation or sham operation, and were assigned to 3 groups (n = 10): sham, sedentary MI (MI-Sed), and exercise MI (MI-Ex). Treadmill training was initiated 1 week post-MI, and gradually increased up to 16 m/min, 5° incline, 50 min/day, 5 days/week, and lasted for a total of 8 weeks. Real-time polymerase chain reaction and gel electrophoresis were performed to quantify changes in TR isoforms. Our results illustrated that mRNA expression of TR-α1 and TR-ß1 was higher in both MIs; however, protein electrophoresis data showed that TR-α1 was 1.91-fold higher (P < 0.05) and TR-ß1 was 1.62-fold higher (P < 0.05) in the MI-Ex group than in the MI-Sed group. After MI, TR-α1 and TR-ß1 protein levels are significantly decreased in the surviving non-infarcted myocardium. Moderate-intensity exercise training significantly increases TR-α1 and TR-ß1 protein expression, which in turn may upregulate α-MHC and improve myocardial contractile function and prognosis.

Exercise training induced myosin heavy chain isoform alteration in the infarcted heart.

The myosin heavy chain isoform MHC-α has 3-fold higher ATPase activity than MHC-ß. After myocardial infarction (MI), MHC-α expression is profoundly downregulated and MHC-ß expression is reciprocally upregulated. This shift, which is attributed to low thyroid hormone (TH), contributes to myocardial systolic dysfunction. We investigated the effect of post-MI exercise training on MHC isoforms, TH, and cardiac function. MI was surgically induced in 7-week-old rats by ligation of the coronary artery. The survivors were assigned to 3 groups (n = 10/group): Sham (no MI, no exercise), MISed (MI, no exercise), and MIEx (MI, exercise). Treadmill exercise training began 1 week post-MI and lasted for 8 weeks. Echocardiogram measurements were taken on the day prior to initiation of exercise training and at the end of exercise training. Tissue and blood samples were collected at the end of the experiment. MHC isoform gene and protein expression and TH were measured. Our results illustrated that MHC-α gene expression was higher and MHC-ß gene expression was lower in the MIEx group than in the MISed group. Resting serum TH concentrations (T3 and T4) were similar between the 2 MI groups. The MIEx group had higher fractional shortening than the MISed group. In conclusion, post-MI exercise training beneficially altered MHC isoforms and improved cardiac function without changing TH.

Exercise training combined with angiotensin II receptor blockade reduces oxidative stress after myocardial infarction in rats.

An increase in oxidative stress and decrease in antioxidant enzymes have been suggested to be involved in the pathophysiology of myocardial infarction (MI). In this study in rats, treadmill exercise training and losartan treatment began 1 week post-myocardial infarction (MI) and lasted 8 weeks. We evaluated the changes in the mRNA and protein expressions for the enzymatic antioxidants superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase after exercise and losartan treatment post-MI. Our results demonstrated that GPx and catalase mRNA levels were comparable among all the groups, while the mRNA level for manganese SOD (MnSOD) was significantly increased in exercise training with/without losartan treatment compared with the sedentary post-MI group. Moreover, the mRNA level for gp91(phox) was dramatically decreased by a combination of exercise and losartan treatment. The protein levels for MnSOD were significantly elevated by exercise training in combination with losartan treatment. The protein levels for catalase were significantly increased in response to exercise, and further augmented by exercise together with losartan treatment. Thiobarbituric acid-reactive substances in plasma were significantly increased in the post-MI rats, but were decreased by exercise or losartan treatment, indicating that both exercise and losartan may reduce lipid oxidative damage. In addition, catalase and SOD enzymatic activities were significantly enhanced by exercise combined with losartan treatment. Our results suggest that exercise training improves catalase and MnSOD expression and attenuates oxidative stress. These effects are potentiated when combining exercise with angiotensin II receptor blockade.

Exercise training combined with angiotensin II receptor blockade limits post-infarct ventricular remodelling in rats.

AIMS: Our aim was to test the hypothesis that angiotensin II receptor blockade combined with exercise training after myocardial infarction (MI) could attenuate post-MI left ventricular remodelling and preserve cardiac function. METHODS AND RESULTS: Sprague-Dawley rats underwent ligation of the left descending coronary artery, resulting in MI, or a sham operation. Losartan treatment and exercise training were initiated 1 week after infarction and continued for 8 weeks, either as a single intervention or combined. Collagen volume fraction in the sedentary MI (MISed) group was significantly higher than other MI groups treated with exercise training and/or losartan. Compared with MISed group, hearts of rats receiving exercise and/or losartan treatment had lower tissue inhibitor of matrix metalloproteinase (TIMP) 1. Matrix metalloproteinase (MMP) 2 or MMP-9 did not differ among all groups. Additionally, the level of angiotensin II receptor type 1 (AT1) protein significantly decreased in response to exercise training. Furthermore, angiotensin converting enzyme (ACE) binding was markedly lower in hearts receiving exercise training than in the MISed hearts. Cardiac function was preserved in rats receiving exercise training, and the beneficial effect was further improved by exercise combined with losartan treatment in comparison to the MISed group. CONCLUSION: Our results suggest that post-MI exercise training and/or AngII receptor blockade reduces TIMP-1 expression and mitigates the expressions of ACE and AT1 receptor. These improvements, in turn, attenuate myocardial fibrosis and preserve post-MI cardiac function.

Effects of exercise training on cardiac function and myocardial remodeling in post myocardial infarction rats.

To test the hypothesis that early exercise training after myocardial infarction (MI) could preserve cardiac function, alleviate left ventricular (LV) remodeling and induce a protective effect on morphology, male Sprague-Dawley rats underwent coronary ligation or sham operation, and were assigned to 3 groups: Sham, sedentary MI (SedMI), and exercise MI (ExMI). We measured the changes in collagen volume fraction, matrix metalloproteinase (MMP) 1, tissue inhibitor matrix metalloproteinase 1 (TIMP-1), angiotensin II receptor type 1 (AT1), and angiotensin converting enzyme (ACE) at gene and protein levels after 8 weeks of exercise training. Cardiac functions were determined by echocardiographic and hemodynamic measurements. Early exercise training after MI had no effect on LV wall thinning. Cardiac function was significantly preserved in the ExMI group in comparison to the SedMI group. The collagen volume fraction in the ExMI group was significantly lower than in the SedMI group. Compared to the SedMI group, the ExMI group showed a markedly decrease at both the gene and protein levels in TIMP-1 (P<0.05). No significant differences were found in MMP-1 among the three groups. MMP-1/TIMP-1 ratio in the ExMI group was significantly higher than in the SedMI group. In addition, the expression of AT1 protein in the ExMI group was significantly lower than in the SedMI group. Furthermore, both ACE mRNA expression and ACE binding in the ExMI group are significantly decreased compared to the SedMI group. Our results suggest that early exercise training after MI reduces TIMP-1 expression, improves the balance between MMPs and TIMPs, and mitigates the expressions of ACE and AT1 receptor. These improvements, in turn, attenuate myocardial fibrosis and preserve post-MI cardiac function.

Effect of post-myocardial infarction exercise training on the renin-angiotensin-aldosterone system and cardiac function.

After a myocardial infarction (MI), the injured heart undergoes intensive remodeling characterized by activation of the circulating renin-angiotensin-aldosterone system (RAAS), left ventricular (LV) dilation, and contractile dysfunction. Exercise training may attenuate activation of the RAAS and improve myocardial remodeling. In this study, we investigated whether starting exercise training early or late after MI would have different effect on circulating RAAS and LV dilation and function. Male Sprague-Dawley rats (7 weeks old) underwent surgically induced MI. After surgery, rats were matched for similar infarct sizes and assigned into two major groups, based on the designated starting time of exercise training. Exercise groups started exercise at either 1 or 6 weeks after MI and exercised on a treadmill for 8 weeks. Groups starting exercise 1 week after MI included sham-operated control (1Wk-Sham), MI-ksedentary (1Wk-MI-Sed), and MI-exercise (1Wk-MI-Ex). Groups starting exercise 6 weeks after MI included sham-operated control (6Wk-Sham), MI-sedentary (6Wk-MI-Sed), and MI-exercise (6Wk-MI-Ex). An echocardiogram was performed before and after exercise training. Blood samples were obtained at the end of experiments. The results showed that compared with sedentary rats with MI, exercise training significantly attenuated circulating renin, angiotensin converting enzyme, angiotensin II, and aldosterone. Rats in exercise groups had similar LV end-diastolic diameters compared with their sedentary counterparts and tended to have smaller LV end-systolic diameters, and percent fractional shortening in exercise rats was significantly higher than in sedentary rats. These findings suggest that exercise training does not cause LV dilation and preserves LV function. Post-MI exercise training also normalizes the circulating RAAS, and this effect is independent of timing of post-MI exercise. Exercise starting early or late after MI affects myocardial remodeling and function similarly, suggesting that early exercise training may attenuate activation of the RAAS and preserve cardiac function early after MI.

Maternal cell traffic bounds for immune modulation: tracking maternal H-2 alleles in spleens of baby mice by DNA fingerprinting.

We have previously reported that the immunization of pregnant mice with T-dependent antigens successfully induced suppression of the antigen-specific plaque-forming cell (PFC) response to the relevant antigens in the offspring. This suppression was not caused by the administered antigens, the antibodies produced by the pregnant mother, or lactational transfer, but was dependent on the presence of the intact maternal T cells. It was major histocompatibility complex (MHC)-restricted manner tolerance, which continued for at least one-sixth of the murine life. Traditionally, the placenta acts as a natural barrier, not allowing the cells to pass through. However, the results presented strongly suggested that maternal T cells pass through the placenta and subsequently induce tolerance. In this present study, we attempted to substantiate the presence of maternal cells in the fetal circulation through the use of molecular techniques. We found that a highly polymorphic microsatellite sequence within the class II Eb gene of the H-2 complex is useful for the molecular detection of various H-2 alleles. DNA polymorphic analysis was used for tracking maternal H-2 alleles in the spleens of baby mice. The main procedure involved polymerase chain reaction amplification and restriction fragment length polymorphism analysis of the DNA sequence encompassing the H-2-specific microsatellite from the genomic DNA of baby mice. The results indicated that maternal T cells of immunized pregnant mice cross the placenta into the fetus, eventually inducing antigen-specific immunological tolerance in the offspring.