Heart function and its susceptibility to arrhythmias are modulated by thyroid hormones (THs) but the responsiveness of hypertensive individuals to thyroid dysfunction is elusive. We aimed to explore the effect of altered thyroid status on crucial factors affecting synchronized heart function, i.e., connexin-43 (Cx43) and extracellular matrix proteins (ECM), in spontaneously hypertensive rats (SHRs) compared to normotensive Wistar Kyoto rats (WKRs). Basal levels of circulating THs were similar in both strains. Hyperthyroid state (HT) was induced by injection of T3 (0.15 mg/kg b.w. for eight weeks) and hypothyroid state (HY) by the administration of methimazol (0.05% for eight weeks). The possible benefit of omega-3 polyunsaturated fatty acids (Omacor, 200 mg/kg for eight weeks) intake was examined as well. Reduced levels of Cx43 in SHRs were unaffected by alterations in THs, unlike WKRs, in which levels of Cx43 and its phosphorylated form at serine368 were decreased in the HT state and increased in the HY state. This specific Cx43 phosphorylation, attributed to enhanced protein kinase C-epsilon signaling, was also increased in HY SHRs. Altered thyroid status did not show significant differences in markers of ECM or collagen deposition in SHRs. WKRs exhibited a decrease in levels of profibrotic transforming growth factor β1 and SMAD2/3 in HT and an increase in HY, along with enhanced interstitial collagen. Short-term intake of omega-3 polyunsaturated fatty acids did not affect any targeted proteins significantly. Key findings suggest that myocardial Cx43 and ECM responses to altered thyroid status are blunted in SHRs compared to WKRs. However, enhanced phosphorylation of Cx43 at serine368 in hypothyroid SHRs might be associated with preservation of intercellular coupling and alleviation of the propensity of the heart to malignant arrhythmias.
- MeSH
- Extracellular Matrix Proteins metabolism MeSH
- Thyroid Hormones blood metabolism MeSH
- Hypertension blood metabolism MeSH
- Connexin 43 metabolism MeSH
- Myocardium metabolism MeSH
- Rats, Inbred SHR MeSH
- Rats, Inbred WKY MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Hypertension, dyslipidemia, and insulin resistance in the spontaneously hypertensive rat (SHR) can be alleviated by rescuing CD36 fatty acid translocase. The present study investigated whether transgenic rescue of CD36 in SHR could affect mitochondrial function and activity of selected metabolic enzymes in the heart. These analyses were conducted on ventricular preparations derived from SHR and from transgenic strain SHR-Cd36 that expresses a functional wild-type CD36. Our respirometric measurements revealed that mitochondria isolated from the left ventricles exhibited two times higher respiratory activity than those isolated from the right ventricles. Whereas, we did not observe any significant changes in functioning of the mitochondrial respiratory system between both rat strains, enzyme activities of total hexokinase, and both mitochondrial and total malate dehydrogenase were markedly decreased in the left ventricles of transgenic rats, compared to SHR. We also detected downregulated expression of the succinate dehydrogenase subunit SdhB (complex II) and 70 kDa peroxisomal membrane protein in the left ventricles of SHR-Cd36. These data indicate that CD36 may affect in a unique fashion metabolic substrate flexibility of the left and right ventricles.
- MeSH
- ATP-Binding Cassette Transporters genetics metabolism MeSH
- CD36 Antigens genetics metabolism MeSH
- Gene Expression MeSH
- Hexokinase genetics metabolism MeSH
- Hypertension enzymology genetics physiopathology MeSH
- Insulin Resistance MeSH
- Myocytes, Cardiac enzymology pathology MeSH
- Rats MeSH
- Malate Dehydrogenase genetics metabolism MeSH
- Mitochondria enzymology pathology MeSH
- Oxidative Phosphorylation MeSH
- Rats, Inbred SHR MeSH
- Rats, Transgenic MeSH
- Primary Cell Culture MeSH
- Gene Expression Regulation MeSH
- Oxygen Consumption genetics MeSH
- Heart Ventricles enzymology pathology MeSH
- Succinate Dehydrogenase genetics metabolism MeSH
- Transgenes * MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
The β-adrenergic signaling pathways and antioxidant defence mechanisms play important roles in maintaining proper heart function. Here, we examined the effect of chronic normobaric hypoxia (CNH, 10% O2, 3 weeks) on myocardial β-adrenergic signaling and selected components of the antioxidant system in spontaneously hypertensive rats (SHR) and in a conplastic SHR-mtBN strain characterized by the selective replacement of the mitochondrial genome of SHR with that of the more ischemia-resistant Brown Norway strain. Our investigations revealed some intriguing differences between the two strains at the level of β-adrenergic receptors (β-ARs), activity of adenylyl cyclase (AC) and monoamine oxidase A (MAO-A), as well as distinct changes after CNH exposure. The β2-AR/β1-AR ratio was significantly higher in SHR-mtBN than in SHR, apparently due to increased expression of β2-ARs. Adaptation to hypoxia elevated β2-ARs in SHR and decreased the total number of β-ARs in SHR-mtBN. In parallel, the ability of isoprenaline to stimulate AC activity was found to be higher in SHR-mtBN than that in SHR. Interestingly, the activity of MAO-A was notably lower in SHR-mtBN than in SHR, and it was markedly elevated in both strains after exposure to hypoxia. In addition to that, CNH markedly enhanced the expression of catalase and aldehyde dehydrogenase-2 in both strains, and decreased the expression of Cu/Zn superoxide dismutase in SHR. Adaptation to CNH intensified oxidative stress to a similar extent in both strains and elevated the IL-10/TNF-α ratio in SHR-mtBN only. These data indicate that alterations in the mitochondrial genome can result in peculiar changes in myocardial β-adrenergic signaling, MAO-A activity and antioxidant defence and may, thus, affect the adaptive responses to hypoxia.
- MeSH
- Adenylyl Cyclases metabolism MeSH
- Receptors, Adrenergic, beta metabolism MeSH
- Hypoxia metabolism MeSH
- Rats MeSH
- Malondialdehyde metabolism MeSH
- Monoamine Oxidase metabolism MeSH
- Myocardium metabolism MeSH
- Rats, Inbred SHR MeSH
- Signal Transduction physiology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Publication type
- Meeting Abstract MeSH
We aimed to study the impact of altered thyroid status on myocardial expression of electrical coupling protein connexin-43 (Cx43), the susceptibility of rats to ventricular fibrillation (VF) and the effects of antioxidant-rich red palm oil (RPO). Adult male and female euthyroid, hyperthyroid (treated with T3/T4), hypothyroid (treated with methimazole) Wistar rats supplemented or not with RPO for 6 weeks were used. Function of isolated perfused heart and VF threshold were determined. Left ventricular tissue was used for assessment of mRNA and protein levels of Cx43, its phosphorylated forms and topology. Protein kinase C signaling (PKC) and gene transcripts of some proteins related to cardiac arrhythmias were assessed. Hyperthyroid state resulted in decrease of total and phosphorylated forms of Cx43 and suppression of PKC-ε expression in males and females, decrease of Cx43 mRNA in females, decrease of VF threshold and increase of functional parameters in male rat hearts. In contrast, hypothyroid status resulted in the increase of total and phosphorylated forms of Cx43, enhancement PKC-ε expression in males and females, increase of Cx43 mRNA in females, increase of VF threshold and decrease of functional parameters in male rat hearts. Function of the heart was partially normalized by RPO intake, which also enhanced myocardial Cx43 and PKC-ε expression as well as increased VF threshold in hyperthyroid male rats. We conclude that there is an inverse relationship between myocardial expression of Cx43, including its functional phosphorylated forms, and susceptibility of male rat hearts to VF in condition of altered thyroid status. RPO intake partly ameliorated adverse changes caused by excess of thyroid hormones.
- MeSH
- Administration, Oral MeSH
- Connexin 43 antagonists & inhibitors genetics metabolism MeSH
- Rats MeSH
- RNA, Messenger antagonists & inhibitors genetics metabolism MeSH
- Myocardium metabolism MeSH
- Plant Oils administration & dosage pharmacology MeSH
- Rats, Wistar MeSH
- Heart drug effects MeSH
- Arrhythmias, Cardiac drug therapy metabolism MeSH
- Thyroid Gland drug effects metabolism MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Adaptation to chronic intermittent hypoxia (CIH) is associated with reactive oxygen species (ROS) generation implicated in the improved cardiac tolerance against acute ischemia-reperfusion injury. Phospholipases A2 (PLA2s) play an important role in cardiomyocyte phospholipid metabolism influencing membrane homeostasis. Here we aimed to determine the effect of CIH (7000 m, 8 h/day, 5 weeks) on the expression of cytosolic PLA2 (cPLA2α), its phosphorylated form (p-cPLA2α), calcium-independent (iPLA2), and secretory (sPLA2IIA) at protein and mRNA levels, as well as fatty acids (FA) profile in left ventricular myocardium of adult male Wistar rats. Chronic administration of antioxidant tempol was used to verify the ROS involvement in CIH effect on PLA2s expression and phospholipid FA remodeling. While CIH did not affect PLA2s mRNA levels, it increased the total cPLA2α protein in cytosol and membranes (by 191% and 38%, respectively) and p-cPLA2α (by 23%) in membranes. On the contrary, both iPLA2 and sPLA2IIA were downregulated by CIH. CIH further decreased phospholipid n-6 polyunsaturated FA (PUFA) and increased n-3 PUFA proportion. Tempol treatment prevented only CIH-induced cPLA2α up-regulation and its phosphorylation on Ser505. Our results show that CIH diversely affect myocardial PLA2s and suggest that ROS are responsible for the activation of cPLA2α under these conditions.
- MeSH
- Antioxidants pharmacology MeSH
- Chronic Disease MeSH
- Cyclic N-Oxides pharmacology MeSH
- Group IV Phospholipases A2 genetics metabolism MeSH
- Phosphorylation drug effects MeSH
- Hypoxia enzymology metabolism MeSH
- Rats MeSH
- Fatty Acids metabolism MeSH
- Rats, Wistar MeSH
- Reactive Oxygen Species metabolism MeSH
- Gene Expression Regulation, Enzymologic drug effects MeSH
- Spin Labels MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Mitochondria play an essential role in improved cardiac ischaemic tolerance conferred by adaptation to chronic hypoxia. In the present study, we analysed the effects of continuous normobaric hypoxia (CNH) on mitochondrial functions, including the sensitivity of the mitochondrial permeability transition pore (MPTP) to opening, and infarct size (IS) in hearts of spontaneously hypertensive rats (SHR) and the conplastic SHR-mt(BN) strain, characterized by the selective replacement of the mitochondrial genome of SHR with that of the more ischaemia-resistant brown Norway (BN) strain. Rats were adapted to CNH (10% O2, 3 weeks) or kept at room air as normoxic controls. In the left ventricular mitochondria, respiration and cytochrome c oxidase (COX) activity were measured using an Oxygraph-2k and the sensitivity of MPTP opening was assessed spectrophotometrically as Ca(2+)-induced swelling. Myocardial infarction was analysed in anaesthetized open-chest rats subjected to 20 min of coronary artery occlusion and 3 h of reperfusion. The IS reached 68±3.0% and 65±5% of the area at risk in normoxic SHR and SHR-mt(BN) strains, respectively. CNH significantly decreased myocardial infarction to 46±3% in SHR. In hypoxic SHR-mt(BN) strain, IS reached 33±2% and was significantly smaller compared with hypoxic SHR. Mitochondria isolated from hypoxic hearts of both strains had increased detergent-stimulated COX activity and were less sensitive to MPTP opening. The maximum swelling rate was significantly lower in hypoxic SHR-mt(BN) strain compared with hypoxic SHR, and positively correlated with myocardial infarction in all experimental groups. In conclusion, the mitochondrial genome of SHR modulates the IS-limiting effect of adaptation to CNH by affecting mitochondrial energetics and MPTP sensitivity to opening.
- MeSH
- Chronic Disease MeSH
- Genome, Mitochondrial genetics MeSH
- Hypoxia * MeSH
- Myocardial Infarction genetics metabolism pathology MeSH
- Rats MeSH
- DNA, Mitochondrial genetics MeSH
- Mitochondrial Proteins genetics metabolism MeSH
- Reverse Transcriptase Polymerase Chain Reaction MeSH
- Rats, Inbred BN MeSH
- Rats, Inbred SHR MeSH
- Rats, Transgenic MeSH
- Myocardial Reperfusion Injury genetics metabolism physiopathology MeSH
- Electron Transport Complex IV genetics metabolism MeSH
- Mitochondria, Heart genetics metabolism MeSH
- Mitochondrial Membrane Transport Proteins metabolism MeSH
- Blotting, Western MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Cardiac resistance against acute ischemia/reperfusion (I/R) injury can be enhanced by adaptation to chronic intermittent hypoxia (CIH), but the changes at the molecular level associated with this adaptation are still not fully explored. Phospholipase A2 (PLA2) plays an important role in phospholipid metabolism and may contribute to membrane destruction under conditions of energy deprivation during I/R. The aim of this study was to determine the effect of CIH (7000 m, 8 h/day, 5 weeks) on the expression of cytosolic PLA2α (cPLA2α) and its phosphorylated form (p-cPLA2α), as well as other related signaling proteins in the left ventricular myocardium of adult male Wistar rats. Adaptation to CIH increased the total content of cPLA2α by 14 % in myocardial homogenate, and enhanced the association of p-cPLA2α with the nuclear membrane by 85 %. The total number of β-adrenoceptors (β-ARs) did not change but the β2/β1 ratio markedly increased due to the elevation of β2-ARs and drop in β1-ARs. In parallel, the amount of adenylyl cyclase decreased by 49 % and Giα proteins increased by about 50 %. Besides that, cyclooxygenase 2 (COX-2) and prostaglandin E2 (PGE2) increased by 36 and 84 %, respectively. In parallel, we detected increased phosphorylation of protein kinase Cα, ERK1/2 and p38 (by 12, 48 and 19 %, respectively). These data suggest that adaptive changes induced in the myocardium by CIH may include activation of cPLA2α and COX-2 via β2-AR/Gi-mediated stimulation of the ERK/p38 pathway.
- MeSH
- Receptors, Adrenergic, beta-2 metabolism MeSH
- Chronic Disease MeSH
- Cyclooxygenase 2 metabolism MeSH
- Group IV Phospholipases A2 metabolism MeSH
- Myocardial Ischemia metabolism pathology MeSH
- Rats MeSH
- MAP Kinase Signaling System * MeSH
- p38 Mitogen-Activated Protein Kinases metabolism MeSH
- Rats, Wistar MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
