Heart failure (HF) is life-threatening disease due to electro-mechanical dysfunction associated with hemodynamic overload, while alterations of extracellular matrix (ECM) along with perturbed connexin-43 (Cx43) might be key factors involved. We aimed to explore a dual impact of pressure, and volume overload due to aorto-caval fistula (ACF) on Cx43 and ECM as well as effect of renin-angiotensin blockade. Hypertensive Ren-2 transgenic rats (TGR) and normotensive Hannover Sprague-Dawley rats (HSD) that underwent ACF were treated for 15-weeks with trandolapril or losartan. Blood serum and heart tissue samples of the right (RV) and left ventricles (LV) were used for analyses. ACF-HF increased RV, LV and lung mass in HSD and to lesser extent in TGR, while treatment attenuated it and normalized serum ANP, BNP-45 and TBARS. Cx43 protein and its ser368 variant along with PKCε were lower in TGR vs HSD and suppressed in both rat strains due to ACF but prevented more by trandolapril. Pro-hypertrophic PKCδ, collagen I and hydroxyproline were elevated in TGR and increased due to ACF in both rat strains. While SMAD2/3 and MMP2 levels were lower in TGR vs HSD and reduced due to ACF in both strains. Findings point out the strain-related differences in response to volume overload. Disorders of Cx43 and ECM signalling may contribute not only to HF but also to the formation of arrhythmogenic substrate. There is benefit of treatment with trandolapril and losartan indicating their pleiotropic anti-arrhythmic potential. It may provide novel input to therapy.
- MeSH
- extracelulární matrix MeSH
- hypertenze * MeSH
- konexin 43 genetika MeSH
- krevní tlak MeSH
- krysa rodu rattus MeSH
- losartan farmakologie MeSH
- píštěle * MeSH
- potkani Sprague-Dawley MeSH
- potkani transgenní MeSH
- renin MeSH
- srdeční selhání * MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The hearts of spontaneously hypertensive rats (SHR) are prone to malignant arrhythmias, mainly due to disorders of electrical coupling protein Cx43 and the extracellular matrix. Cold acclimation may induce cardio-protection, but the underlying mechanisms remain to be elucidated. We aimed to explore whether the adaptation of 9-month-old hairless SHRM to cold impacts the fundamental cardiac pro-arrhythmia factors, as well as the response to the thyroid status. There were no significant differences in the registered biometric, redox and blood lipids parameters between hairless (SHRM) and wild type SHR. Prominent findings revealed that myocardial Cx43 and its variant phosphorylated at serine 368 were increased, while an abnormal cardiomyocyte Cx43 distribution was attenuated in hairless SHRM vs. wild type SHR males and females. Moreover, the level of β-catenin, ensuring mechanoelectrical coupling, was increased as well, while extracellular matrix collagen-1 and hydroxyproline were lower and the TGF-β1 and SMAD2/3 pathway was suppressed in hairless SHRM males compared to the wild type strain. Of interest, the extracellular matrix remodeling was less pronounced in females of both hypertensive strains. There were no apparent differences in response to the hypothyroid or hyperthyroid status between SHR strains concerning the examined markers. Our findings imply that hairless SHRM benefit from cold acclimation due to the attenuation of the hypertension-induced adverse downregulation of Cx43 and upregulation of extracellular matrix proteins.
- Publikační typ
- časopisecké články MeSH
We aimed to explore whether specific high-sucrose intake in older female rats affects myocardial electrical coupling protein, connexin-43 (Cx43), protein kinase C (PKC) signaling, miR-1 and miR-30a expression, and susceptibility of the heart to malignant arrhythmias. Possible benefit of the supplementation with melatonin (40 μg/ml/day) and omega-3 polyunsaturated fatty acids (Omacor, 25 g/kg of rat chow) was examined as well. Results have shown that 8 weeks lasting intake of 30% sucrose solution increased serum cholesterol, triglycerides, body weight, heart weight, and retroperitoneal adipose tissues. It was accompanied by downregulation of cardiac Cx43 and PKCε signaling along with an upregulation of myocardial PKCδ and miR-30a rendering the heart prone to ventricular arrhythmias. There was a clear benefit of melatonin or omega-3 PUFA supplementation due to their antiarrhythmic effects associated with the attenuation of myocardial Cx43, PKC, and miR-30a abnormalities as well as adiposity. The potential impact of these findings may be considerable, and suggests that high-sucrose intake impairs myocardial signaling mediated by Cx43 and PKC contributing to increased susceptibility of the older obese female rat hearts to malignant arrhythmias.
- MeSH
- antiarytmika metabolismus farmakologie MeSH
- konexin 43 metabolismus MeSH
- konzumní sacharóza škodlivé účinky MeSH
- krysa rodu rattus MeSH
- melatonin metabolismus farmakologie MeSH
- mikro RNA metabolismus MeSH
- myokard metabolismus MeSH
- obezita chemicky indukované komplikace farmakoterapie metabolismus MeSH
- omega-3 mastné kyseliny metabolismus farmakologie MeSH
- potkani Wistar MeSH
- proteinkinasa C-delta metabolismus MeSH
- proteinkinasa C-epsilon metabolismus MeSH
- signální transdukce účinky léků MeSH
- srdce účinky léků MeSH
- srdeční arytmie etiologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
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
- extracelulární matrix - proteiny metabolismus MeSH
- hormony štítné žlázy krev metabolismus MeSH
- hypertenze krev metabolismus MeSH
- konexin 43 metabolismus MeSH
- myokard metabolismus MeSH
- potkani inbrední SHR MeSH
- potkani inbrední WKY MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Remodeling of the cellular distribution of gap junctions formed mainly by connexin-43 (Cx43) can be related to the increased incidence of cardiac arrhythmias. It has been shown that adaptation to chronic intermittent hypobaric hypoxia (IHH) attenuates the incidence and severity of ischemic and reperfusion ventricular arrhythmias and increases the proportion of anti-arrhythmic n-3 polyunsaturated fatty acids (n-3 PUFA) in heart phospholipids. Wistar rats were exposed to simulated IHH (7,000 m, 8-h/day, 35 exposures) and compared with normoxic controls (N). Cx43 expression, phosphorylation, localization and n-3 PUFA proportion were analyzed in left ventricular myocardium. Compared to N, IHH led to higher expression of total Cx43, its variant phosphorylated at Ser368 [p-Cx43(Ser368)], which maintains "end to end" communication, as well as p-Cx43(Ser364/365), which facilitates conductivity. By contrast, expression of non-phosphorylated Cx43 and p-Cx43(Ser278/289), attenuating intercellular communication, was lower in IHH than in N. IHH also resulted in increased expression of protein kinase A and protein kinase G while casein kinase 1 did not change compared to N. In IHH group, which exhibited reduced incidence of ischemic ventricular arrhythmias, Cx43 and p-Cx43(Ser368) were more abundant at "end to end" gap junctions than in N group and this difference was preserved after acute regional ischemia (10 min). We further confirmed higher n-3 PUFA proportion in heart phospholipids after adaptation to IHH, which was even further increased by ischemia. Our results suggest that adaptation to IHH alters expression, phosphorylation and distribution of Cx43 as well as cardioprotective n-3PUFA proportion suggesting that the anti-arrhythmic phenotype elicited by IHH can be at least partly related to the stabilization of the "end to end" conductivity between cardiomyocytes during brief ischemia.
- Publikační typ
- časopisecké články MeSH
