BACKGROUND: Cardiometabolic risk factors - including diabetes, hypertension, and obesity - have long been linked with adverse health outcomes such as strokes, but more subtle brain changes in regional brain volumes and cortical thickness associated with these risk factors are less understood. Computer models can now be used to estimate brain age based on structural magnetic resonance imaging data, and subtle brain changes related to cardiometabolic risk factors may manifest as an older-appearing brain in prediction models; thus, we sought to investigate the relationship between cardiometabolic risk factors and machine learning-predicted brain age. METHODS: We performed a systematic search of PubMed and Scopus. We used the brain age gap, which represents the difference between one's predicted and chronological age, as an index of brain structural integrity. We calculated the Cohen d statistic for mean differences in the brain age gap of people with and without diabetes, hypertension, or obesity and performed random effects meta-analyses. RESULTS: We identified 185 studies, of which 14 met inclusion criteria. Among the 3 cardiometabolic risk factors, diabetes had the highest effect size (12 study samples; d = 0.275, 95% confidence interval [CI] 0.198-0.352; n = 47 436), followed by hypertension (10 study samples; d = 0.113, 95% CI 0.063-0.162; n = 45 102) and obesity (5 study samples; d = 0.112, 95% CI 0.037-0.187; n = 15 678). These effects remained significant in sensitivity analyses that included only studies that controlled for confounding effects of the other cardiometabolic risk factors. LIMITATIONS: Our study tested effect sizes of only categorically defined cardiometabolic risk factors and is limited by inconsistencies in diabetes classification, a smaller pooled sample in the obesity analysis, and limited age range reporting. CONCLUSION: Our findings show that each of the cardiometabolic risk factors uniquely contributes to brain structure, as captured by brain age. The effect size for diabetes was more than 2 times greater than the independent effects of hypertension and obesity. We therefore highlight diabetes as a primary target for the prevention of brain structural changes that may lead to cognitive decline and dementia.
- MeSH
- diabetes mellitus * epidemiologie patologie MeSH
- hypertenze * epidemiologie patologie MeSH
- kardiometabolické riziko * MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- mozek * diagnostické zobrazování patologie MeSH
- obezita * epidemiologie patologie MeSH
- stárnutí patologie MeSH
- strojové učení MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- systematický přehled MeSH
Nestin is a unique intermediate filament expressed for a short period in the developing heart. It was also documented in several cell types of the adult myocardium under pathological conditions such as myocardial infarction or fibrosis. However, circumstances of nestin re-occurrence in the diseased or aging heart have not been elucidated yet. In this work we immunohistochemically detected nestin to determine its expression and distribution pattern in the left ventricular myocardium of normotensive Wistar Kyoto (WKY) rats and in the hypertrophic ones of spontaneously hypertensive (SHR) rats, both at the age of 1 and 1.5 year. No nestin+ cells were identified in the intact myocardium of 1-year-old WKY rats, whereas in the aged 1.5-year-old WKY rats nestin+ endothelial cells in some blood vessels were discovered. In the hypertrophic myocardium of all SHR rats, nestin was rarely detected in desmin+ vimentin- cardiomyocytes and in some vimentin+ interstitial cells often accumulated in clusters, varying in intensity of desmin immunoreactivity. Moreover, nestin was infrequently expressed in the endothelial cells of some myocardial blood vessels in 1-year-old SHR rats, but not in 1.5-year-old ones. Quantitative image analysis of nestin expression in the myocardium confirmed significant increase in 1.5-year-old WKY rats and in SHR rats of both ages compared to the intact 1-year-old WKY rats. This study firstly documents nestin re-expression indicating cytoskeletal remodelling in different cell types of the aging intact and chronically pressure over-loaded hypertrophied myocardium. Our findings confirm nestin involvement in complex changes during myocardial hypertrophy and progressive aging.
- Klíčová slova
- Desmin, Myocardial hypertrophy, Myocardium, Nestin, Vimentin,
- MeSH
- hypertenze metabolismus patologie MeSH
- kardiomyocyty metabolismus patologie MeSH
- krysa rodu Rattus MeSH
- myokard * metabolismus patologie MeSH
- nestin * metabolismus MeSH
- potkani inbrední SHR MeSH
- potkani inbrední WKY MeSH
- proteiny intermediálních filament metabolismus MeSH
- proteiny nervové tkáně metabolismus MeSH
- stárnutí * metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- Nes protein, rat MeSH Prohlížeč
- nestin * MeSH
- proteiny intermediálních filament MeSH
- proteiny nervové tkáně MeSH
Telmisartan is an angiotensin receptor blocker (ARB) and a selective peroxisome proliferator activated receptor gamma (PPARG) modulator. Recently, we tested metabolic effects of telmisartan (5 mg/kg body weight) in spontaneously hypertensive rats (SHR) fed a diet containing 60 % fructose, a widely used model of the metabolic syndrome. Surprisingly, we observed acute toxic effects of telmisartan. Rats lost body weight rapidly and died within 2 to 3 weeks due to bleeding into the upper gastrointestinal tract. SHR fed a high fructose diet and treated with telmisartan exhibited rapid decrease in blood pressure when compared to the SHR fed a high fructose diet and treated with valsartan. Concentrations of both unconjugated telmisartan and telmisartan glucuronide in the liver of SHR rats fed a high fructose diet were approximately 4 fold higher when compared to Brown Norway (BN) rats fed the same diet. Plasma concentrations of unconjugated telmisartan in the SHR were about 5 fold higher when compared to BN rats while plasma levels of telmisartan glucuronide were similar between the strains. Testing of other rat strains, diets, and the ARB valsartan showed that toxic effects of telmisartan in combination with high fructose diet are specific for the SHR. These results are consistent with the possibility that in some circumstances, SHR are predisposed to telmisartan toxicity possibly because of a genetically determined disturbance in telmisartan metabolism.
- MeSH
- antihypertenziva toxicita MeSH
- dietní cukry aplikace a dávkování toxicita MeSH
- fruktosa aplikace a dávkování toxicita MeSH
- gastrointestinální trakt účinky léků patologie MeSH
- hypertenze genetika patologie MeSH
- krysa rodu Rattus MeSH
- potkani inbrední SHR MeSH
- potkani Wistar MeSH
- telmisartan toxicita MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antihypertenziva MeSH
- dietní cukry MeSH
- fruktosa MeSH
- telmisartan MeSH
Structural changes of thoracic aorta (TA), carotid (CA) and iliac artery (IA) were assessed in Wistar and spontaneously hypertensive rats (SHR) aged 3, 17, and 52 weeks. Systolic blood pressure (sBP) was measured by plethysmography weekly. After perfusion fixation the arteries were processed for electron microscopy. The wall thickness (WT), cross-sectional area (CSA), inner diameter (ID), and WT/ID in all arteries and volume densities of endothelial cells (ECs), muscle cells (SMCs), and extracellular matrix (ECM) in TA were measured and their CSAs were calculated. In 3-week-old SHR compared to Wistar rats, sBP did not differ; in the TA, all parameters (WT, CSA, ID, WT/ID, CSA of SMCs, CSA of ECs, and CSA of ECM) were decreased; in CA, WT and CSA did not differ, ID was decreased, and WT/ID was increased; in IA, WT, CSA, and ID were increased. In 17- and 52-week-old SHRs, sBP and all parameters in all arteries were increased, only ID in IE in 52-week-old SHRs and CSA of ECs in the TA in 17-week-old SHRs did not change. Disproportionality between BP increase and structural alterations during ontogeny in SHR could reflect the flexibility of the arterial tree to the different needs of supplied areas.
- MeSH
- aorta thoracica patologie patofyziologie MeSH
- arteria iliaca patologie patofyziologie MeSH
- arteriae carotides patologie patofyziologie MeSH
- hypertenze patologie patofyziologie MeSH
- krevní tlak fyziologie MeSH
- krysa rodu Rattus MeSH
- potkani inbrední SHR MeSH
- potkani Wistar MeSH
- tunica intima patologie patofyziologie MeSH
- věkové faktory MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
The dentate gyrus of the hippocampus is one of the few places in the brain where neurogenesis occurs in adulthood. Nowadays, an increasing number of children and young adults are affected by hypertension, one of the factors in the development of cerebrovascular diseases and age-related cognitive deficits. Since these cognitive deficits are often hippocampus-dependent, it is possible that hypertension exerts this effect via decreasing adult neurogenesis which has been shown to be essential for a range of cognitive tasks. We used spontaneously hypertensive rats, which develop hypertension in the first weeks of life. Half of them were treated with the antihypertensive drug captopril. We found that the drug-induced lowering of blood pressure in this period did not affect the rate of adult neurogenesis. In a second experiment, we used another animal model of hypertension - salt-sensitive and salt-resistant strains of Dahl rats. A high-salt diet induces hypertension in the salt-sensitive strain, but not in the salt-resistant strain. The high-salt diet led to salt-induced hypertension, but did not affect the level of adult neurogenesis in the dentate gyrus of the hippocampus. We conclude that hypertension does not significantly affect the rate of hippocampal neurogenesis in young adult rats.
- MeSH
- hipokampus patologie fyziologie MeSH
- hypertenze patologie patofyziologie MeSH
- krevní tlak fyziologie MeSH
- krysa rodu Rattus MeSH
- náhodné rozdělení MeSH
- neurogeneze fyziologie MeSH
- potkani inbrední Dahl MeSH
- potkani inbrední SHR MeSH
- věkové faktory MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Chronic low-grade inflammation plays an important role in the pathogenesis of insulin resistance. In the current study, we tested the effects of salsalate, a non-steroidal anti-inflammatory drug, in an animal model of inflammation and metabolic syndrome using spontaneously hypertensive rats (SHR) that transgenically express human C-reactive protein (SHR-CRP rats). We treated 15-month-old male transgenic SHR-CRP rats and nontransgenic SHR with salsalate (200 mg/kg/day) mixed as part of a standard diet for 4 weeks. A corresponding untreated control group of male transgenic SHR-CRP and SHR rats were fed a standard diet without salsalate. In the SHR-CRP transgenic strain, salsalate treatment decreased circulating concentrations of the inflammatory markers TNF-α and MCP-1, reduced oxidative stress in the liver and kidney, increased sensitivity of skeletal muscles to insulin action and improved tolerance to glucose. In SHR controls with no CRP-induced inflammation, salsalate treatment reduced body weight, decreased concentrations of serum free fatty acids and total and HDL cholesterol and increased palmitate oxidation and incorporation in brown adipose tissue. Salsalate regulated inflammation by affecting the expression of genes from MAPK signalling and NOD-like receptor signalling pathways and lipid metabolism by affecting hepatic expression of genes that favour lipid oxidation from PPAR-α signalling pathways. These findings suggest that salsalate has metabolic effects beyond suppressing inflammation.
- MeSH
- C-reaktivní protein biosyntéza genetika MeSH
- geneticky modifikovaná zvířata genetika MeSH
- hnědá tuková tkáň metabolismus MeSH
- hypertenze farmakoterapie genetika patologie MeSH
- inzulinová rezistence genetika MeSH
- játra metabolismus MeSH
- krysa rodu Rattus MeSH
- kyseliny mastné neesterifikované metabolismus MeSH
- lidé MeSH
- metabolický syndrom farmakoterapie genetika patologie MeSH
- metabolismus lipidů účinky léků MeSH
- NLR proteiny biosyntéza MeSH
- oxidační stres účinky léků MeSH
- PPAR alfa biosyntéza MeSH
- salicylany aplikace a dávkování MeSH
- TNF-alfa biosyntéza MeSH
- zánět farmakoterapie genetika patologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- C-reaktivní protein MeSH
- kyseliny mastné neesterifikované MeSH
- NLR proteiny MeSH
- PPAR alfa MeSH
- salicylany MeSH
- salicylsalicylic acid MeSH Prohlížeč
- TNF-alfa MeSH
The spontaneously hypertensive rat (SHR), one of the most widely used model of essential hypertension, is predisposed to left ventricular hypertrophy, myocardial fibrosis, and metabolic disturbances. Recently, quantitative trait loci influencing blood pressure, left ventricular mass, and heart interstitial fibrosis were genetically isolated within a minimal congenic subline that contains only 7 genes, including mutant Plzf (promyelocytic leukemia zinc finger) candidate gene. To identify Plzf as a quantitative trait gene, we targeted Plzf in the SHR using the transcription activator-like effector nuclease technique and obtained SHR line harboring targeted Plzf gene with a premature stop codon. Because the Plzf targeted allele is semilethal, morphologically normal heterozygous rats were used for metabolic and hemodynamic analyses. SHR-Plzf+/- heterozygotes versus SHR wild-type controls exhibited reduced body weight and relative weight of epididymal fat, lower serum and liver triglycerides and cholesterol, and better glucose tolerance. In addition, SHR-Plzf+/- rats exhibited significantly increased sensitivity of adipose and muscle tissue to insulin action when compared with wild-type controls. Blood pressure was comparable in SHR versus SHR-Plzf+/-; however, there was significant amelioration of cardiomyocyte hypertrophy and cardiac fibrosis in SHR-Plzf+/- rats. Gene expression profiles in the liver and expression of selected genes in the heart revealed differentially expressed genes that play a role in metabolic pathways, PPAR (peroxisome proliferator-activated receptor) signaling, and cell cycle regulation. These results provide evidence for an important role of Plzf in regulation of metabolic and cardiac traits in the rat and suggest a cross talk between cell cycle regulators, metabolism, cardiac hypertrophy, and fibrosis.
- Klíčová slova
- fibrosis, hypertension, hypertrophy, left ventricular, rats, inbred SHR, transcriptome,
- MeSH
- alely MeSH
- analýza rozptylu MeSH
- down regulace MeSH
- esenciální hypertenze MeSH
- fenotyp MeSH
- fibróza genetika MeSH
- hypertenze genetika patologie MeSH
- hypertrofie levé komory srdeční genetika patofyziologie MeSH
- kardiomyocyty metabolismus MeSH
- krysa rodu Rattus MeSH
- kultivované buňky MeSH
- kvantitativní polymerázová řetězová reakce metody MeSH
- lokus kvantitativního znaku MeSH
- měření krevního tlaku MeSH
- metabolismus lipidů genetika MeSH
- potkani inbrední SHR MeSH
- protein promyelocytické leukemie s motivem zinkového prstu MeSH
- stanovení celkové genové exprese * MeSH
- transkripční faktory Krüppel-like genetika MeSH
- western blotting MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- protein promyelocytické leukemie s motivem zinkového prstu MeSH
- transkripční faktory Krüppel-like MeSH
- Zbtb16 protein, mouse MeSH Prohlížeč
Solid organ transplantation is an established treatment modality in patients with end-stage organ damage in cases where other therapeutic options fail. The long-term outcomes of solid organ transplant recipients have improved considerably since the introduction of the first calcineurin inhibitor (CNI) - cyclosporine. In 1984, the potent immunosuppressive properties of another CNI, tacrolimus, were discovered. The immunosuppressive effects of CNIs result from the inhibition of interleukin-2 synthesis and reduced proliferation of T cells due to calcineurin blockade. The considerable side effects that are associated with CNIs therapy include arterial hypertension and nephrotoxicity. The focus of this article was to review the available literature on the pathophysiological mechanisms of CNIs that induce chronic nephrotoxicity and arterial hypertension. CNIs lead to activation of the major vasoconstriction systems, such as the renin-angiotensin and endothelin systems, and increase sympathetic nerve activity. On the other hand, CNIs are known to inhibit NO synthesis and NO-mediated vasodilation and to increase free radical formation. Altogether, these processes cause endothelial dysfunction and contribute to the impairment of organ function. A better insight into the mechanisms underlying CNI nephrotoxicity could assist in developing more targeted therapies of arterial hypertension or preventing CNI nephrotoxicity in organ transplant recipients, including heart transplantation.
- MeSH
- hypertenze chemicky indukované patologie patofyziologie MeSH
- imunosupresiva škodlivé účinky MeSH
- inhibitory kalcineurinu aplikace a dávkování škodlivé účinky MeSH
- lidé MeSH
- nemoci ledvin chemicky indukované patologie patofyziologie MeSH
- reaktivní formy kyslíku metabolismus MeSH
- rejekce štěpu etiologie prevence a kontrola MeSH
- renin-angiotensin systém účinky léků MeSH
- transplantace srdce škodlivé účinky MeSH
- vazokonstrikce účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- imunosupresiva MeSH
- inhibitory kalcineurinu MeSH
- reaktivní formy kyslíku MeSH
Calcium sensitization mediated by RhoA/Rho kinase pathway can be evaluated either in the absence (basal calcium sensitization) or in the presence of endogenous vasoconstrictor systems (activated calcium sensitization). Our aim was to compare basal and activated calcium sensitization in three forms of experimental hypertension with increased sympathetic tone and enhanced calcium entry-spontaneously hypertensive rats (SHR), heterozygous Ren-2 transgenic rats (TGR), and salt hypertensive Dahl rats. Activated calcium sensitization was determined as blood pressure reduction induced by acute administration of Rho kinase inhibitor fasudil in conscious rats with intact sympathetic nervous system (SNS) and renin-angiotensin system (RAS). Basal calcium sensitization was studied as fasudil-dependent difference in blood pressure response to calcium channel opener BAY K8644 in rats subjected to RAS and SNS blockade. Calcium sensitization was also estimated from reduced development of isolated artery contraction by Rho kinase inhibitor Y-27632. Activated calcium sensitization was enhanced in all three hypertensive models (due to the hyperactivity of vasoconstrictor systems). In contrast, basal calcium sensitization was reduced in SHR and TGR relative to their controls, whereas it was augmented in salt-sensitive Dahl rats relative to their salt-resistant controls. Similar differences in calcium sensitization were seen in femoral arteries of SHR and Dahl rats.
- MeSH
- geneticky modifikovaná zvířata MeSH
- hypertenze etiologie genetika metabolismus patologie MeSH
- kinázy asociované s Rho antagonisté a inhibitory genetika MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- potkani inbrední Dahl MeSH
- potkani inbrední SHR MeSH
- signální transdukce účinky léků MeSH
- sympatický nervový systém metabolismus patologie MeSH
- vápník aplikace a dávkování metabolismus MeSH
- vazokonstrikce genetika MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- kinázy asociované s Rho MeSH
- vápník MeSH
Gap junction connexin channels are important determinants of myocardial conduction and synchronization that is crucial for coordinated heart function. One of the main risk factors for cardiovascular events that results in heart attack, congestive heart failure, stroke as well as sudden arrhythmic death is hypertension. Mislocalization and/or dysfunction of specific connexin-43 channels due to hypertension-induced myocardial remodeling have been implicated in the occurrence of life-threatening arrhythmias and heart failure in both, humans as well as experimental animals. Recent studies suggest that down-regulation of myocardial connexin-43, its abnormal distribution and/or phosphorylation might be implicated in this process. On the other hand, treatment of hypertensive animals with cardioprotective drugs (e.g. statins) or supplementation with non-pharmacological compounds, such as melatonin, omega-3 fatty acids and red palm oil protects from lethal arrhythmias. The antiarrhythmic effects are attributed to the attenuation of myocardial connexin-43 abnormalities associated with preservation of myocardial architecture and improvement of cardiac conduction. Findings uncover novel mechanisms of cardioprotective (antihypertensive and antiarrhythmic) effects of compounds that are used in clinical settings. Well-designed trials are needed to explore the antiarrhythmic potential of these compounds in patients suffering from hypertension.
- MeSH
- antiarytmika farmakologie terapeutické užití MeSH
- antioxidancia farmakologie terapeutické užití MeSH
- hypertenze farmakoterapie metabolismus patologie MeSH
- konexin 43 metabolismus MeSH
- lidé MeSH
- melatonin farmakologie terapeutické užití MeSH
- mezerový spoj ultrastruktura MeSH
- myokard ultrastruktura MeSH
- oleje rostlin farmakologie terapeutické užití MeSH
- omega-3 mastné kyseliny farmakologie terapeutické užití MeSH
- srdce účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- antiarytmika MeSH
- antioxidancia MeSH
- GJA1 protein, human MeSH Prohlížeč
- konexin 43 MeSH
- melatonin MeSH
- oleje rostlin MeSH
- omega-3 mastné kyseliny MeSH
