C. Xinaris

Thyroid hormone receptors α1 and β1 are downregulated in the post-infarcted rat heart: consequences on the response to ischaemia-reperfusion

There is accumulating evidence that thyroid hormone metabolism is altered after myocardial infarction (AMI) but its physiological relevance remains largely unknown. The present study investigated the possible role of thyroid hormone signaling in the response of the post-infarcted heart to ischaemia-reperfusion. Wistar rats were subjected to left coronary artery ligation (AMI), or sham operation (SHAM). After 8 weeks, hearts from AMI and SHAM rats were perfused in Langendorff mode and subjected to 20 min of zero-flow global ischaemia (I) and 45 min of reperfusion (R); AMI(I/R), n = 7 and SHAM(I/R), n = 7. Basal left ventricular pressure (LVDP), +dp/dt, and –dp/dt were significantly reduced. Left ventricular weight of the viable myocardium was increased by 14% in the AMI as compared to SHAM hearts, P < 0.05. T3 and T4 plasma levels in nM were 1.83 (0.08) and 53.3 (2.9) for SHAM and 1.76 (0.06) and 59.4 (5.2) for AMI rats, respectively, P > 0.05. TRα1 and TRβ1 expression levels were 1.3- and 1.8-fold less in AMI than in SHAM hearts, P < 0.05. Furthermore, SERCA and NHE1 expression levels were 2.1- and 1.8-fold less in AMI than in SHAM, P < 0.05. PKCε was 1.35-fold more in AMI compared to SHAM, P < 0.05. Myocardial glycogen content (in µmol/g) was 7.8 (1.2) in AMI as compared to 4.4 (0.5) for SHAM hearts, P < 0.05. After I/R, left ventricular end-diastolic pressure at 45 min of R (LVEDP45 in mmHg) was 20.3 (3.2) for AMI(I/R) vs 50.6 (4.8) mmHg for SHAM(I/R), P < 0.05. LDH release per gram of tissue was 251 (103) for AMI(I/R) and 762 (74) for SHAM(I/R), P < 0.05. In conclusion, TRα1 and TRβ1 are downregulated after myocardial infarction and this was associated with altered expression of thyroid hormone responsive genes and increased tolerance of the post-infarcted heart to ischaemia-reperfusion injury.

Time-dependent changes in the expression of thyroid hormone receptor α1 in the myocardium after acute myocardial infarction: possible implications in cardiac remodelling

The present study investigated whether changes in thyroid hormone (TH) signalling can occur after acute myocardial infarction (AMI) with possible physiological consequences on myocardial performance. TH may regulate several genes encoding important structural and regulatory proteins particularly through the TR alpha 1 receptor which is predominant in the myocardium. AMI was induced in rats by ligating the left coronary artery while sham-operated animals served as controls. This resulted in impaired cardiac function in AMI animals after 2 and 13 weeks accompanied by a shift in myosin isoforms expression towards a fetal phenotype in the non-infarcted area. Cardiac hypertrophy was evident in AMI hearts after 13 weeks but not at 2 weeks. This response was associated with a differential pattern of TH changes at 2 and 13 weeks; T(3) and T(4) levels in plasma were not changed at 2 weeks but T(3) was significantly lower and T(4) remained unchanged at 13 weeks. A twofold increase in TR alpha 1 expression was observed after 13 weeks in the non-infarcted area, P<0.05 versus sham operated, while TR alpha 1 expression remained unchanged at 2 weeks. A 2.2-fold decrease in TR beta 1 expression was found in the non-infarcted area at 13 weeks, P<0.05, while no change in TR beta 1 expression was seen at 2 weeks. Parallel studies with neonatal cardiomyocytes showed that phenylephrine (PE) administration resulted in 4.5-fold increase in the expression of TR alpha 1 and 1.6-fold decrease in TR beta 1 expression versus untreated, P<0.05. In conclusion, cardiac dysfunction which occurs at late stages after AMI is associated with increased expression of TR alpha 1 receptor and lower circulating tri-iodothyronine levels. Thus, apo-TR alpha 1 receptor state may prevail contributing to cardiac fetal phenotype. Furthermore, down-regulation of TR beta 1 also contributes to fetal phenotypic changes. alpha1-adrenergic signalling is, at least in part, involved in this response.

Enhanced tolerance of the rat myocardium to ischemia and reperfusion injury early after acute myocardial infarction

AbstractIt is now recognized that changes occurring during cardiac remodeling may influence the tolerance of the myocardium to ischemic stress. Therefore, the present study investigated the response of the post-infarcted heart to ischemia in an experimental model of ischemia and reperfusion injury and the possible underlying mechanisms. Acute myocardial infarction (AMI) was induced in Wistar male rats by ligating the left coronary artery (AMI, n = 13), while sham-operated rats were used as controls (SHAM, n = 11). At 2 weeks, cardiac dysfunction was observed in AMI, as indicated by the reduction of the left ventricular EF%. Isolated hearts were then subjected to 30 min of zero-flow global ischemia followed by 45 min of reperfusion. Ischemic contracture was significantly depressed in AMI hearts. Postischemic left ventricular end diastolic pressure (LVEDP45) in mmHg and LDH release in IU/g were markedly decreased; LVEDP45 was 52.1 (7.5) for AMI vs 96.6 (7.5),P < 0.05 and LDH release was 7.5 (1.0) in AMI vs 11.4 (0.56) in SHAM, P < 0.05. This response was associated with 2-fold increase in HSP70 expression in AMI hearts (noninfarcted segment), P < 0.05 vs SHAM and 1.7 fold increase in the expression of the phospho-HSP27, P < 0.05, while the expression of PKCε was shown to be 1.4-fold less in AMI, P < 0.05. In conclusion, the post-infarcted heart seems to be resistant to ischemiareperfusion injury and heat shock protein 70 and 27 may be involved in this response.

High glucose protects embryonic cardiac cells against simulated ischemia

In the present study we investigated whether acute glucose administration could be protective against hypoxic stress. H9c2 cells were exposed to either 4.5,mM or 22,mM of glucose for 15,min and then were submitted to simulated ischemia. Cell death was microscopically assessed by combined staining with propidium iodide (PI) and Hoeschst 33358. Intracellular content of glucose was measured by enzymatic analysis. Clucose content of H9c2 cells was 48.24± 7.94,μmol/L in the 22,mM vs 23.86± 4.8,μmol/L in the 4.5,mM group (p < 0.05). PKCε expression was increased 1.6 fold in the membrane fraction after pretreatment with high glucose (p < 0.05), while was decreased 1.6 fold in the cytosol (p < 0.05). In addition, no difference to PKCδ translocation was observed after pretreatment with low glucose. After hypoxia, in the 22,mM group, cell death was found to be 17.36± 2.66% vs 38.2± 5.4% in the 4.5,mM group (p < 0.05). In the presence of iodoacetic acid, a glycolytic inhibitor, cell death was not different between the two groups (23.54± 3.2% in 22,mM vs 22.06± 5.3% in 4.5,mM). Addition of chelerythrine did not change the protective effect of high glucose (13.4± 1.7% cell death in 22,mM vs 27.5± 5.5% in 4.5,mM, p < 0.05). In conclusion, short pretreatment with high glucose protects H9c2 cells against hypoxia. Although this protective effect is associated with translocation of PKCε and increased glucose uptake, it was abrogated only by inhibition of glycolysis. (Mol Cell Biochem xxx: 1–7, 2005)

Thyroid hormone and myocardial ischaemia

Thyroid hormone has various effects on the cardiovascular system and its effects on cardiac contractility, heart rhythm and vascular function has long been recognized. However, new evidence is emerged on the importance of thyroid hormone in the response of the myocardium to ischaemic stress and cardiac remodelling following myocardial infarction. Based on this new information, this review highlights the role of thyroid hormone in myocardial ischaemia and cardiac remodelling, the possible underlying mechanisms and the potential therapeutic implications. Thyroid hormone or analogs may prove new therapeutic agents for treating ischaemic heart disease.