A combination of liver and heart dysfunction worsens the prognosis of human survival. The aim of this study was to investigate whether empagliflozin (a sodium-glucose transporter-2 inhibitor) has beneficial effects not only on cardiac and renal function but also on hepatic function. Adult (6-month-old) male spontaneously hypertensive rats (SHR) were fed a high-fat diet (60% fat) for four months to induce hepatic steatosis and mild heart failure. For the last two months, the rats were treated with empagliflozin (empa, 10 mg.kg-1.day-1 in the drinking water). Renal function and oral glucose tolerance test were analyzed in control (n=8), high-fat diet (SHR+HF, n=10), and empagliflozin-treated (SHR+HF+empa, n=9) SHR throughout the study. Metabolic parameters and echocardiography were evaluated at the end of the experiment. High-fat diet feeding increased body weight and visceral adiposity, liver triglyceride and cholesterol concentrations, and worsened glucose tolerance. Although the high-fat diet did not affect renal function, it significantly worsened cardiac function in a subset of SHR rats. Empagliflozin reduced body weight gain but not visceral fat deposition. It also improved glucose sensitivity and several metabolic parameters (plasma insulin, uric acid, and HDL cholesterol). In the liver, empagliflozin reduced ectopic lipid accumulation, lipoperoxidation, inflammation and pro-inflammatory HETEs, while increasing anti-inflammatory EETs. In addition, empagliflozin improved cardiac function (systolic, diastolic and pumping) independent of blood pressure. The results of our study suggest that hepatoprotection plays a decisive role in the beneficial effects of empagliflozin in preventing the progression of cardiac dysfunction induced by high-fat diet feeding.
- Klíčová slova
- Cardiac function, Kidney function, Liver steatosis, Metabolic parameters, SGLT-2 inhibition,
- MeSH
- benzhydrylové sloučeniny * farmakologie MeSH
- dieta s vysokým obsahem tuků * škodlivé účinky MeSH
- glifloziny * farmakologie MeSH
- glukosidy * farmakologie MeSH
- hypertenze farmakoterapie MeSH
- játra * účinky léků metabolismus patologie MeSH
- kardiotonika farmakologie MeSH
- krevní glukóza metabolismus účinky léků MeSH
- krevní tlak účinky léků MeSH
- krysa rodu Rattus MeSH
- ledviny účinky léků metabolismus patologie MeSH
- ochranné látky farmakologie MeSH
- potkani inbrední SHR * MeSH
- ztučnělá játra prevence a kontrola farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- benzhydrylové sloučeniny * MeSH
- empagliflozin MeSH Prohlížeč
- glifloziny * MeSH
- glukosidy * MeSH
- kardiotonika MeSH
- krevní glukóza MeSH
- ochranné látky MeSH
The aim of the study was to clarify the role of the interplay between hypertension and the renin-angiotensin system (RAS) in the pathophysiology of myocardial ischemia/reperfusion (I/R) injury. We hypothesized that in the late phase of hypertension with already developed signs of end-organ damage, inappropriate RAS activation could impair cardiac tolerance to I/R injury. Experiments were performed in male Cyp1a1-Ren-2 transgenic rats with inducible hypertension. The early phase of ANG II-dependent hypertension was induced by 5 days and the late phase by the 13 days dietary indole-3-carbinol (I3C) administration. Noninduced rats served as controls. Echocardiography and pressure-volume analysis were performed, angiotensins' levels were measured and cardiac tolerance to ischemia/reperfusion injury was studied. The infarct size was significantly reduced (by 50%) in 13 days I3C-induced hypertensive rats with marked cardiac hypertrophy, this reduction was abolished by losartan treatment. In the late phase of hypertension there are indications of a failing heart, mainly in reduced preload recruitable stroke work (PRSW), but only nonsignificant trends in worsening of some other parameters, showing that the myocardium is in a compensated phase. The influence of the RAS depends on the balance between the vasoconstrictive and the opposed vasodilatory axis. In the initial stage of hypertension, the vasodilatory axis of the RAS prevails, and with the development of hypertension the vasoconstrictive axis of the RAS becomes stronger. We observed a clear effect of AT1 receptor blockade on maximum pressure in left ventricle, cardiac hypertrophy and ANG II levels. In conclusion, we confirmed improved cardiac tolerance to I/R injury in hypertensive hypertrophied rats and showed that, in the late phase of hypertension, the myocardium is in a compensated phase.
- Klíčová slova
- ANG II-dependent hypertension, AT1 receptor antagonist, P-V analysis, ischemia/reperfusion injury, renin-angiotensin system,
- Publikační typ
- časopisecké články MeSH
Mutations of the TMEM70 gene disrupt the biogenesis of the ATP synthase and represent the most frequent cause of autosomal recessive encephalo-cardio-myopathy with neonatal onset. Patient tissues show isolated defects in the ATP synthase, leading to the impaired mitochondrial synthesis of ATP and insufficient energy provision. In the current study, we tested the efficiency of gene complementation by using a transgenic rescue approach in spontaneously hypertensive rats with the targeted Tmem70 gene (SHR-Tmem70ko/ko), which leads to embryonic lethality. We generated SHR-Tmem70ko/ko knockout rats expressing the Tmem70 wild-type transgene (SHR-Tmem70ko/ko,tg/tg) under the control of the EF-1α universal promoter. Transgenic rescue resulted in viable animals that showed the variable expression of the Tmem70 transgene across the range of tissues and only minor differences in terms of the growth parameters. The TMEM70 protein was restored to 16-49% of the controls in the liver and heart, which was sufficient for the full biochemical complementation of ATP synthase biogenesis as well as for mitochondrial energetic function in the liver. In the heart, we observed partial biochemical complementation, especially in SHR-Tmem70ko/ko,tg/0 hemizygotes. As a result, this led to a minor impairment in left ventricle function. Overall, the transgenic rescue of Tmem70 in SHR-Tmem70ko/ko knockout rats resulted in the efficient complementation of ATP synthase deficiency and thus in the successful genetic treatment of an otherwise fatal mitochondrial disorder.
- Klíčová slova
- ATP synthase deficiency, TMEM70 factor, gene therapy, mitochondria disease, transgenic rescue,
- Publikační typ
- časopisecké články MeSH
Cardiovascular and heart diseases are leading causes of morbidity and mortality. Coronary artery endothelial and vascular dysfunction, inflammation, and mitochondrial dysfunction contribute to progression of heart diseases such as arrhythmias, congestive heart failure, and heart attacks. Classes of fatty acid epoxylipids and their enzymatic regulation by soluble epoxide hydrolase (sEH) have been implicated in coronary artery dysfunction, inflammation, and mitochondrial dysfunction in heart diseases. Likewise, genetic and pharmacological manipulations of epoxylipids have been demonstrated to have therapeutic benefits for heart diseases. Increasing epoxylipids reduce cardiac hypertrophy and fibrosis and improve cardiac function. Beneficial actions for epoxylipids have been demonstrated in cardiac ischemia reperfusion injury, electrical conductance abnormalities and arrhythmias, and ventricular tachycardia. This review discusses past and recent findings on the contribution of epoxylipids in heart diseases and the potential for their manipulation to treat heart attacks, arrhythmias, ventricular tachycardia, and heart failure.
- Klíčová slova
- Coronary artery, Cytochrome P450, Eicosanoids, Heart failure, Hypertension, Inflammation, Mitochondrial function, Myocardial infarction, Soluble epoxide hydrolase,
- MeSH
- epoxid hydrolasy antagonisté a inhibitory metabolismus MeSH
- epoxidové sloučeniny chemie metabolismus MeSH
- infarkt myokardu farmakoterapie enzymologie metabolismus MeSH
- inhibitory enzymů terapeutické užití MeSH
- komorová tachykardie farmakoterapie enzymologie metabolismus MeSH
- lidé MeSH
- mastné kyseliny metabolismus MeSH
- nemoci srdce farmakoterapie enzymologie metabolismus MeSH
- rozpustnost MeSH
- srdeční arytmie farmakoterapie enzymologie metabolismus MeSH
- srdeční selhání farmakoterapie enzymologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- epoxid hydrolasy MeSH
- epoxidové sloučeniny MeSH
- inhibitory enzymů MeSH
- mastné kyseliny MeSH
The new antidiabetic drugs, gliflozins, inhibit sodium-glucose transporter-2 in renal proximal tubules promoting glucose and sodium excretion. This leads not only to a significant improvement of glucose control but also to the reduction of blood pressure and body weight in both diabetic patients and experimental models. We examined whether these beneficial effects can also be achieved in a non-diabetic hypertensive model, namely in Ren-2 transgenic rats (TGR). Adult 6-month-old hypertensive TGR and their normotensive controls (Hannover Sprague-Dawley rats), were either untreated or treated with empagliflozin (10 mg/kg/day) for two months. Telemetric blood pressure monitoring, renal parameters as well as cardiac function via echocardiography were analyzed during the experiment. At the end of the study, the contribution of major vasoactive systems to blood pressure maintenance was studied. Metabolic parameters and markers of oxidative stress and inflammation were also analyzed. Empagliflozin had no effect on plasma glucose level but partially reduced blood pressure in TGR. Although food consumption was substantially higher in empagliflozin-treated TGR compared to the untreated animals, their body weight and the amount of epididymal and perirenal fat was decreased. Empagliflozin had no effect on proteinuria, but it decreased plasma urea, attenuated renal oxidative stress and temporarily increased urinary urea excretion. Several metabolic (hepatic triglycerides, non-esterified fatty acids, insulin) and inflammatory (TNF-α, leptin) parameters were also improved by empagliflozin treatment. By contrast, echocardiography did not reveal any effect of empagliflozin on cardiac function. In conclusion, empagliflozin exerted beneficial antihypertensive, anti-inflammatory and metabolic effects also in a non-diabetic hypertensive model.
- Klíčová slova
- Cardiac, Renal and metabolic parameters, SGLT-2 inhibitor,
- MeSH
- adipozita účinky léků MeSH
- antiflogistika farmakologie MeSH
- antihypertenziva farmakologie MeSH
- antioxidancia farmakologie MeSH
- benzhydrylové sloučeniny farmakologie MeSH
- energetický metabolismus účinky léků MeSH
- glukosidy farmakologie MeSH
- hmotnostní úbytek účinky léků MeSH
- hypertenze farmakoterapie genetika metabolismus patofyziologie MeSH
- krevní tlak účinky léků MeSH
- krysa rodu Rattus MeSH
- modely nemocí na zvířatech MeSH
- potkani Sprague-Dawley MeSH
- potkani transgenní MeSH
- renin genetika MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antiflogistika MeSH
- antihypertenziva MeSH
- antioxidancia MeSH
- benzhydrylové sloučeniny MeSH
- empagliflozin MeSH Prohlížeč
- glukosidy MeSH
- renin MeSH
Aging attenuates cardiac tolerance to ischemia/reperfusion (I/R) associated with defects in protective cell signaling, however, the onset of this phenotype has not been completely investigated. This study aimed to compare changes in response to I/R and the effects of remote ischemic preconditioning (RIPC) in the hearts of younger adult (3 months) and mature adult (6 months) male Wistar rats, with changes in selected proteins of protective signaling. Langendorff-perfused hearts were exposed to 30 min I/120 min R without or with prior three cycles of RIPC (pressure cuff inflation/deflation on the hind limb). Infarct size (IS), incidence of ventricular arrhythmias and recovery of contractile function (LVDP) served as the end points. In both age groups, left ventricular tissue samples were collected prior to ischemia (baseline) and after I/R, in non-RIPC controls and in RIPC groups to detect selected pro-survival proteins (Western blot). Maturation did not affect post-ischemic recovery of heart function (Left Ventricular Developed Pressure, LVDP), however, it increased IS and arrhythmogenesis accompanied by decreased levels and activity of several pro-survival proteins and by higher levels of pro-apoptotic proteins in the hearts of elder animals. RIPC reduced the occurrence of reperfusion-induced ventricular arrhythmias, IS and contractile dysfunction in younger animals, and this was preserved in the mature adults. RIPC did not increase phosphorylated protein kinase B (p-Akt)/total Akt ratio, endothelial nitric oxide synthase (eNOS) and protein kinase Cε (PKCε) prior to ischemia but only after I/R, while phosphorylated glycogen synthase kinase-3β (GSK3β) was increased (inactivated) before and after ischemia in both age groups coupled with decreased levels of pro-apoptotic markers. We assume that resistance of rat heart to I/R injury starts to already decline during maturation, and that RIPC may represent a clinically relevant cardioprotective intervention in the elder population.
- Klíčová slova
- ischemia/reperfusion injury, maturation, protective cell signaling, remote ischemic preconditioning,
- MeSH
- fosforylace MeSH
- GSK3B genetika metabolismus MeSH
- hemodynamika MeSH
- ischemické přivykání * MeSH
- krysa rodu Rattus MeSH
- myokard metabolismus MeSH
- potkani Wistar MeSH
- proteinkinasa C-epsilon genetika metabolismus MeSH
- protoonkogenní proteiny c-akt genetika metabolismus MeSH
- reperfuzní poškození myokardu metabolismus patologie MeSH
- stárnutí MeSH
- synthasa oxidu dusnatého, typ III genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- GSK3B MeSH
- proteinkinasa C-epsilon MeSH
- protoonkogenní proteiny c-akt MeSH
- synthasa oxidu dusnatého, typ III MeSH
Increased level of C-reactive protein (CRP) is a risk factor for cardiovascular diseases, including myocardial infarction and hypertension. Here, we analyzed the effects of CRP overexpression on cardiac susceptibility to ischemia/reperfusion (I/R) injury in adult spontaneously hypertensive rats (SHR) expressing human CRP transgene (SHR-CRP). Using an in vivo model of coronary artery occlusion, we found that transgenic expression of CRP predisposed SHR-CRP to repeated and prolonged ventricular tachyarrhythmias. Excessive ischemic arrhythmias in SHR-CRP led to a significant reduction in infarct size (IS) compared with SHR. The proarrhythmic phenotype in SHR-CRP was associated with altered heart and plasma eicosanoids, myocardial composition of fatty acids (FAs) in phospholipids, and autonomic nervous system imbalance before ischemia. To explain unexpected IS-limiting effect in SHR-CRP, we performed metabolomic analysis of plasma before and after ischemia. We also determined cardiac ischemic tolerance in hearts subjected to remote ischemic perconditioning (RIPer) and in hearts ex vivo. Acute ischemia in SHR-CRP markedly increased plasma levels of multiple potent cardioprotective molecules that could reduce IS at reperfusion. RIPer provided IS-limiting effect in SHR that was comparable with myocardial infarction observed in naïve SHR-CRP. In hearts ex vivo, IS did not differ between the strains, suggesting that extra-cardiac factors play a crucial role in protection. Our study shows that transgenic expression of human CRP predisposes SHR-CRP to excess ischemic ventricular tachyarrhythmias associated with a drop of pump function that triggers myocardial salvage against lethal I/R injury likely mediated by protective substances released to blood from hypoxic organs and tissue at reperfusion.
- Klíčová slova
- C-reactive protein, heart, metabolomics, myocardial infarction, remote ischemic perconditioning, ventricular arrhythmias,
- MeSH
- akční potenciály MeSH
- C-reaktivní protein genetika metabolismus MeSH
- fibrilace komor etiologie metabolismus patofyziologie MeSH
- hypertenze komplikace metabolismus patofyziologie MeSH
- komorová tachykardie etiologie metabolismus patofyziologie MeSH
- krevní tlak MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myokard metabolismus patologie MeSH
- potkani inbrední SHR MeSH
- potkani transgenní MeSH
- reperfuzní poškození myokardu etiologie metabolismus patofyziologie prevence a kontrola MeSH
- srdeční frekvence MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- C-reaktivní protein MeSH
We investigated the role of the interaction between hypertension and the renin-angiotensin system in the pathophysiology of myocardial ischemia/reperfusion injury. We hypothesized that in the early phase of angiotensin II (ANG II)-dependent hypertension with developed left ventricular hypertrophy, cardioprotective mechanism(s) are fully activated. The experiments were performed in transgenic rats with inducible hypertension, noninduced rats served as controls. The early phase of ANG II-dependent hypertension was induced by five-days (5 days) dietary indole-3-carbinol administration. Cardiac hypertrophy, ANG II and ANG 1-7 levels, protein expression of their receptors and enzymes were determined. Separate groups were subjected to acute myocardial ischemia/reperfusion injury, and infarct size and ventricular arrhythmias were assessed. Induced rats developed marked cardiac hypertrophy accompanied by elevated ANG levels. Ischemia/reperfusion mortality was significantly higher in induced than noninduced rats (52.1 and 25%, respectively). The blockade of AT1 receptors with losartan significantly increased survival rate in both groups. Myocardial infarct size was significantly reduced after 5 days induction (by 11%), without changes after losartan treatment. In conclusion, we confirmed improved cardiac tolerance to ischemia/reperfusion injury in hypertensive cardiohypertrophied rats and found that activation of AT1 receptors by locally produced ANG II in the heart was not the mechanism underlying infarct size reduction.
- Klíčová slova
- angiotensin II receptor antagonist, hypertension, infarct size, ischemia/reperfusion injury, renin-angiotensin system,
- Publikační typ
- časopisecké články MeSH
The main aim was to find out whether long-lasting stepwise exposure to extreme hypoxia affects left ventricular (LV) geometry and systolic function. Adult male rats were exposed to intermittent hypobaric hypoxia (8 h/day) with increasing altitude in steps of 1000 m every 3 weeks up to 8000 m. While the LV cavity diastolic diameter did not change over the whole range of hypoxia, the wall thickness increased significantly at the altitude of 8000 m. LV fractional shortening ranged between 48.1 % and 50.1 % and remained unaffected even at the most severe hypoxia. At the end of experiment, haematocrit reached 83 %, mean systemic arterial pressure 120 % and relative LV weight 154 % of normoxic values while RV systolic pressure and relative RV weight doubled. Myocyte hypertrophy and myocardial fibrosis were more pronounced in RV than in LV. In conclusion, LV systolic function was preserved after chronic stepwise exposure of rats to extreme intermittent hypoxia despite moderate concentric hypertrophy and myocardial remodelling.
- Klíčová slova
- Chronic hypoxia, Extreme altitude, Heart function, Myocardial remodelling,
- MeSH
- funkce levé komory srdeční fyziologie MeSH
- funkce pravé komory srdeční fyziologie MeSH
- hypoxie krev patofyziologie MeSH
- krysa rodu Rattus MeSH
- nadmořská výška * MeSH
- potkani Wistar MeSH
- remodelace komor fyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
While necroptosis has been shown to contribute to the pathogenesis of post-infarction heart failure (HF), the role of autophagy remains unclear. Likewise, linkage between these two cell death modalities has not been sufficiently investigated. HF was induced by 60-min left coronary occlusion in adult Wistar rats and heart function was assessed 6 weeks later followed by immunoblotting analysis of necroptotic and autophagic proteins in both the left (LV) and right ventricle (RV). HF had no effect on RIP1 and RIP3 expression. PhosphoSer229-RIP3, acting as a pro-necroptotic signal, was increased in LV while deceased in RV of failing hearts. Total MLKL was elevated in RV only. Decrease in pSer555-ULK1, increase in pSer473-Akt and no significant elevation in beclin-1 and LC3-II/I ratio indicated rather a lowered rate of autophagy in LV. No beclin-1 upregulation and decreased LC3 processing also suggested the inhibition of both autophagosome formation and maturation in RV of failing hearts. In contrast, p89 PARP1 fragment, a marker of executed apoptosis, was increased in RV only. This is the first study showing a different signaling in ventricles of the late phase of post-infarction HF, highlighting necroptosis itself rather than its linkage with autophagy in LV, and apoptosis in RV.
- Klíčová slova
- autophagy, cell death, heart failure, necroptosis,
- MeSH
- apoptóza * fyziologie MeSH
- autofagie fyziologie MeSH
- infarkt myokardu komplikace patologie MeSH
- nekroptóza fyziologie MeSH
- potkani Sprague-Dawley MeSH
- potkani Wistar MeSH
- protein-serin-threoninkinasy interagující s receptory metabolismus MeSH
- protein-serin-threoninkinasy metabolismus MeSH
- signální transdukce MeSH
- srdeční komory patologie MeSH
- srdeční selhání etiologie metabolismus patologie MeSH
- velikost orgánu MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- protein-serin-threoninkinasy interagující s receptory MeSH
- protein-serin-threoninkinasy MeSH
- RIPK1 protein, rat MeSH Prohlížeč
- Ripk3 protein, rat MeSH Prohlížeč
