Cardiac remodeling induced by smoking: Concepts, relevance, and potential mechanisms

Cardiac or ventricular remodeling is characterized by molecular, cellular, and interstitial alterations that lead to changes in heart size, mass, geometry and function in response to a given insult. Currently, tobacco smoke exposure is recognized as one of these insults. Indeed, tobacco smoke exposure induces the enlargement of the left-sided cardiac chambers, myocardial hypertrophy, and ventricular dysfunction. Potential mechanisms for these alterations include hemodynamic and neurohormonal changes, oxidative stress, inflammation, nitric oxide bioavailability, matrix metalloproteinases and mitogen-activated protein kinase activation. This review will focus on the concepts, relevance, and potential mechanisms of cardiac remodeling induced by tobacco smoke. © 2012 Bentham Science Publishers.

Myogenin, MyoD and IGF-I regulate muscle mass but not fiber-type conversion during resistance training in rats

The purpose of this study was to test the hypothesis that skeletal muscle adaptations induced by long-term resistance training (RT) are associated with increased myogenic regulatory factors (MRF) and insulin-like growth factor-I (IGF-I) mRNA expression in rats skeletal muscle. Male Wistar rats were divided into 4 groups: 8-week control (C8), 8-week trained (T8), 12-week control (C12) and 12-week trained (T12). Trained rats were submitted to a progressive RT program (4 sets of 10-12 repetitions at 65-75% of the 1RM, 3 day/week), using a squat-training apparatus with electric stimulation. Muscle hypertrophy was determined by measurement of muscle fiber cross-sectional area (CSA) of the muscle fibers, and myogenin, MyoD and IGF-I mRNA expression were measured by RT-qPCR. A hypertrophic stabilization occurred between 8 and 12 weeks of RT (control-relative % area increase, T8: 29% vs. T12: 35%; p>0.05) and was accompanied by the stabilization of myogenin (control-relative % increase, T8: 44.8% vs. T12: 37.7%, p>0.05) and MyoD (control-relative % increase, T8: 22.9% vs. T12: 22.3%, p>0.05) mRNA expression and the return of IGF-I mRNA levels to the baseline (control-relative % increase, T8: 30.1% vs. T12: 1.5%, p<0.05). Moreover, there were significant positive correlations between the muscle fiber CSA and mRNA expression for MyoD (r=0.85, p=0.0001), myogenin (r=0.87, p=0.0001), and IGF-I (r=0.88, p=0.0001). The significant (p<0.05) increase in myogenin, MyoD and IGF-I mRNA expression after 8 weeks was not associated with changes in the fiber-type frequency. In addition, there was a type IIX/D-to-IIA fiber conversion at 12 weeks, even with the stabilization of MyoD and myogenin expression and the return of IGF-I levels to baseline. These results indicate a possible interaction between MRFs and IGF-I in the control of muscle hypertrophy during long-term RT and suggest that these factors are involved more in the regulation of muscle mass than in fiber-type conversion. © Georg Thieme Verlag KG Stuttgart · New York.

Macrophage migration inhibitory factor in the nucleus of solitary tract decreases blood pressure in SHRs

Aims The macrophage migration inhibitory factor (MIF) is an intracellular inhibitor of the central nervous system actions of angiotensin II on blood pressure. Considering that angiotensin II actions at the nucleus of the solitary tract are important for the maintenance of hypertension in spontaneously hypertensive rats (SHRs), we tested if increased MIF expression in the nucleus of the solitary tract of SHR alters the baseline high blood pressure in these rats.Methods and resultsEight-week-old SHRs or normotensive rats were microinjected with the vector AAV2-CBA-MIF into the nucleus of the solitary tract, resulting in MIF expression predominantly in neurons. Rats also underwent recordings of the mean arterial blood pressure (MAP) and heart rate (via telemetry devices implanted in the abdominal aorta), cardiac- and baroreflex function. Injections of AAV2-CBA-MIF into the nucleus of the solitary tract of SHRs produced significant decreases in the MAP, ranging from 10 to 20 mmHg, compared with age-matched SHRs that had received identical microinjections of the control vector AAV2-CBA-eGFP. This lowered MAP in SHRs was maintained through the end of the experiment at 31 days, and was associated with an improvement in baroreflex function to values observed in normotensive rats. In contrast to SHRs, similar increased MIF expression in the nucleus of the solitary tract of normotensive rats produced no changes in baseline MAP and baroreflex function.ConclusionThese results indicate that an increased expression of MIF within the nucleus of the solitary tract neurons of SHRs lowers blood pressure and restores baroreflex function. © 2012 Published on behalf of the European Society of Cardiology. All rights reserved.

Infliximab prevents increased systolic blood pressure and upregulates the AKT/eNOS pathway in the aorta of spontaneously hypertensive rats

High systolic blood pressure caused by endothelial dysfunction is a comorbidity of metabolic syndrome that is mediated by local inflammatory signals. Insulin-induced vasorelaxation due to endothelial nitric oxide synthase (eNOS) activation is highly dependent on the activation of the upstream insulin-stimulated serine/threonine kinase (AKT) and is severely impaired in obese, hypertensive rodents and humans. Neutralisation of circulating tumor necrosis factor-α (TNFα) with infliximab improves glucose homeostasis, but the consequences of this pharmacological strategy on systolic blood pressure and eNOS activation are unknown. To address this issue, we assessed the temporal changes in the systolic pressure of spontaneously hypertensive rats (SHR) treated with infliximab. We also assessed the activation of critical proteins that mediate insulin activity and TNFα-mediated insulin resistance in the aorta and cardiac left ventricle. Our data demonstrate that infliximab prevents the upregulation of both systolic pressure and left ventricle hypertrophy in SHR. These effects paralleled an increase in AKT/eNOS phosphorylation and a reduction in the phosphorylation of inhibitor of nuclear factor-κB (Iκβ) and c-Jun N-terminal kinase (JNK) in the aorta. Overall, our study revealed the cardiovascular benefits of infliximab in SHR. In addition, the present findings further suggested that the reduction of systolic pressure and left ventricle hypertrophy by infliximab are secondary effects to the reduction of endothelial inflammation and the recovery of AKT/eNOS pathway activation. © 2012 Elsevier B.V.

The reproductive cycle of the male sleep snake Sibynomorphus mikanii (Schlegel, 1837) from southeastern brazil

This study describes the male reproductive cycle of Sibynomorphus mikanii from southeastern Brazil considering macroscopic and microscopic variables. Spermatogenesis occurs during spring-summer (September-December) and spermiogenesis or maturation occurs in summer (December-February). The length and width of the kidney, the tubular diameter, and the epithelium height of the sexual segment of the kidney (SSK) are larger in summer-autumn (December-May). Histochemical reaction of the SSK [periodic acid-Schiff (PAS) and bromophenol blue (BB)] shows stronger results during summer-autumn, indicating an increase in the secretory activity of the granules. Testicular regression is observed in autumn and early winter (March-June) when a peak in the width of the ductus deferens occurs. The distal ductus deferens as well as the ampulla ductus deferentis exhibit secretory activities with positive reaction for PAS and BB. These results suggest that this secretion may nourish the spermatozoa while they are being stored in the ductus deferens. The increase in the Leydig cell nuclear diameter in association with SSK hypertrophy and the presence of sperm in the female indicate that the mating season occurs in autumn when testes begin to decrease their activity. The peak activity of Leydig cells and SSK exhibits an associated pattern with the mating season. However, spermatogenesis is dissociated of the copulation characterizing a complex reproductive cycle. At the individual level, S. mikanii males present a continuous cyclical reproductive pattern in the testes and kidneys (SSK), whereas at the populational level the reproductive pattern may be classified as seasonal semisynchronous. © 2012 Wiley Periodicals, Inc.

Cardiac remodeling induced by 13-cis retinoic acid treatment in acne patients

Background: Currently, 13-cis-retinoic acid (13-cis-RA) is the most effective therapy for acne. Isotretinoin, a first-generation synthetic 13-cis-RA compound, is associated with numerous adverse effects. To investigate the cardiac effects of 13-cis-RA, acne patients receiving 13-cis-RA were studied. Methods: Twenty male patients with acne were enrolled in the study. Patients were treated with a dose of 0.5 mg/kg/d of isotretinoin. All participants were assessed prior to treatment and after 10 weeks of therapy with Doppler-echocardiogram. Results: Patients showed reductions in right atrium vertical diameter, left atrium longitudinal diameter, left atrium volume and left ventricular diastolic diameter over the course of treatment. Significant increases in interventricular septum diastolic thickness, posterior wall diastolic thickness, relative wall relative thickness and left ventricle (LV) mass were observed. The LV mass index showed an increase in ventricular mass and a decrease in the cavity size. Examining LV systolic function, a decrease was observed for the cardiac index. Conclusion: In this study, 10 weeks of 13-cis-RA therapy at a dose of 0.5 mg/kg/d was found to promote concentric-type heart remodeling due to the occurrence of two associated events: heart hypertrophy and hypovolemia. © 2011 Elsevier B.V. All rights reserved.

Clinical and molecular study of a new form of hereditary myotonia in Murrah water buffalo

Hereditary myotonia caused by mutations in CLCN1 has been previously described in humans, goats, dogs, mice and horses. The goal of this study was to characterize the clinical, morphological and genetic features of hereditary myotonia in Murrah buffalo. Clinical and laboratory evaluations were performed on affected and normal animals. CLCN1 cDNA and the relevant genomic region from normal and affected animals were sequenced. The affected animals exhibited muscle hypertrophy and stiffness. Myotonic discharges were observed during EMG, and dystrophic changes were not present in skeletal muscle biopsies; the last 43 nucleotides of exon-3 of the CLCN1 mRNA were deleted. Cloning of the genomic fragment revealed that the exclusion of this exonic sequence was caused by aberrant splicing, which was associated with the presence of a synonymous SNP in exon-3 (c.396C>T). The mutant allele triggered the efficient use of an ectopic 5' splice donor site located at nucleotides 90-91 of exon-3. The predicted impact of this aberrant splicing event is the alteration of the CLCN1 translational reading frame, which results in the incorporation of 24 unrelated amino acids followed by a premature stop codon. Copyright © 2012 Elsevier B.V. All rights reserved.

Extensive impact of saturated fatty acids on metabolic and cardiovascular profile in rats with diet-induced obesity: A canonical analysis

Background: Although hypercaloric interventions are associated with nutritional, endocrine, metabolic, and cardiovascular disorders in obesity experiments, a rational distinction between the effects of excess adiposity and the individual roles of dietary macronutrients in relation to these disturbances has not previously been studied. This investigation analyzed the correlation between ingested macronutrients (including sucrose and saturated and unsaturated fatty acids) plus body adiposity and metabolic, hormonal, and cardiovascular effects in rats with diet-induced obesity. Methods: Normotensive Wistar-Kyoto rats were submitted to Control (CD; 3.2 Kcal/g) and Hypercaloric (HD; 4.6 Kcal/g) diets for 20 weeks followed by nutritional evaluation involving body weight and adiposity measurement. Metabolic and hormonal parameters included glycemia, insulin, insulin resistance, and leptin. Cardiovascular analysis included systolic blood pressure profile, echocardiography, morphometric study of myocardial morphology, and myosin heavy chain (MHC) protein expression. Canonical correlation analysis was used to evaluate the relationships between dietary macronutrients plus adiposity and metabolic, hormonal, and cardiovascular parameters. Results: Although final group body weights did not differ, HD presented higher adiposity than CD. Diet induced hyperglycemia while insulin and leptin levels remained unchanged. In a cardiovascular context, systolic blood pressure increased with time only in HD. Additionally, in vivo echocardiography revealed cardiac hypertrophy and improved systolic performance in HD compared to CD; and while cardiomyocyte size was unchanged by diet, nuclear volume and collagen interstitial fraction both increased in HD. Also HD exhibited higher relative β-MHC content and β/α-MHC ratio than their Control counterparts. Importantly, body adiposity was weakly associated with cardiovascular effects, as saturated fatty acid intake was directly associated with most cardiac remodeling measurements while unsaturated lipid consumption was inversely correlated with these effects. Conclusion: Hypercaloric diet was associated with glycemic metabolism and systolic blood pressure disorders and cardiac remodeling. These effects directly and inversely correlated with saturated and unsaturated lipid consumption, respectively. © 2013 Oliveira Junior et al.; licensee BioMed Central Ltd.

Alterations in the duodenum myenteric neurons of Wistar rats after ingesting of 2,4 dichlorophenoxyacetic acid

The 2,4 dichlorophenoxyacetic acid (2,4-D) is a systemic herbicide whose effects in animal organic systems have been examined in previous studies, being the neurotoxicity considered the predominant effect. However, the studies that detect the 2,4-D neurotoxicity have merely focused in the central nervous system, and therefore, little is known about the effect of this herbicide in the enteric nervous system. This study aimed to verifying the 2,4-D effects on the myenteric neurons in duodenum of Wistar rats. Ten 60-day-old male Wistar rats (Rattus norvegicus) were divided in two groups: control group (C) that did not receive 2,4-D and experimental group (E) that received 5.0 mg of 2,4-D/kg for 15 days. At the end of experimental period, the animal were euthanized, the duodenum was collected and processed for NADPH-diaphorase histochemical analysis in order to expose the nitrergic myenteric neurons (NADPH-dp). In the light microscopy analysis, the whole-mount preparation obtained from duodenum of each animal were image-captured in 120 and 40 fields, for quantitative and morphometric analyses of myenteric neurons, respectively. The neuronal density was not affected when comparing the two groups, but an increase (p > 0.05) of 8.5% was observed in the cell body area of neurons in the E group. In conclusion, the ingestion of 2,4-D at a dosage of 5.0 mg/kg body weight for 15 days does not change the neuronal density, but promotes the hypertrophy of NADPH-dp myenteric neurons in duodenum of the rats of this study.

A novel function for CUGBP2 in controlling the pro-inflammatory stimulus in H9c2 cells: Subcellular trafficking of messenger molecules

Accumulating evidence demonstrates that chronic inflammation plays an important role in heart hypertrophy and cardiac diseases. However, the fine-tuning of cellular and molecular mechanisms that connect inflammatory process and cardiac diseases is still under investigation. Many reports have demonstrated that the overexpression of the cyclooxygenase-2 (COX-2), a key enzyme in the conversion of arachidonic acid to prostaglandins and other prostanoids, is correlated with inflammatory processes. Increased level of prostaglandin E2 was also found in animal model of left ventricle of hypertrophy. Based on previous observations that demonstrated a regulatory loop between COX-2 and the RNA-binding protein CUGBP2, we studied cellular and molecular mechanisms of a pro-inflammatory stimulus in a cardiac cell to verify if the above two molecules could be correlated with the inflammatory process in the heart. A cellular model of investigation was established and H9c2 was used.We also demonstrated a regulatory connection between COX-2 and CUGBP2 in the cardiac cells. Based on a set of different assays including gene silencing and fluorescence microscopy, we describe a novel function for the RNA-binding protein CUGBP2 in controlling the pro-inflammatory stimulus: subcellular trafficking of messenger molecules to specific cytoplasmic stress granules to maintain homeostasis. © 2013 International Federation for Cell Biology.

Impact of the length of vitamin D deficiency on cardiac remodeling.

This study was aimed to evaluate the influence of vitamin D (VD) deficiency on cardiac metabolism, morphology, and function. Thus, we investigated the relationship of these changes with the length of the nutrient restriction. Male weanling Wistar rats were allocated into 4 groups: C2 (n=24), animals were fed an AIN-93G diet with 1000 IU VD/kg of chow and were kept under fluorescent light for 2 months; D2 (n=22), animals were fed a VD-deficient AIN-93G diet and were kept under incandescent light for 2 months; C4 (n=21) animals were kept in the same conditions of C2 for 4 months; and D4 (n=23) animals were kept in the same conditions of D2 for 4 months. Biochemical analyses showed lower β-hydroxyacyl coenzyme-A dehydrogenase activity and higher lactate dehydrogenase activity in VD-deficient animals. Furthermore, VD deficiency was related to increased cytokines release, oxidative stress, apoptosis, and fibrosis. Echocardiographic data showed left ventricular hypertrophy and lower fractional shortening and ejection fraction in VD-deficient animals. Difference became evident in the lactate dehydrogenase activity, left ventricular weight, right ventricle weight, and left ventricular mass after 4 months of VD deficiency. Our data indicate that VD deficiency is associated with energetic metabolic changes, cardiac inflammation, oxidative stress, fibrosis and apoptosis, cardiac hypertrophy, left chambers alterations, and systolic dysfunction. Furthermore, length of the restriction influenced these cardiac changes.

The action of aminoguanidine on the liver of trained diabetic rats

Background: This study evaluated the effect of aminoguanidine on liver of diabetic rats subject to physical exercises using histological and histochemical techniques.Methods: The rats used in this study were divided into five groups: sedentary control, sedentary diabetic, trained diabetic, sedentary diabetic and treated with aminoguanidine, trained diabetic and treated with aminoguanidine.Results: The results showed no effect of aminoguanidine on the liver tissue, although there was improvement with exercise training showing cytological, morpho-histological and histochemical alterations in liver cells of animals from groups trained diabetic and/or treated diabetic compared to those individuals in the sedentary control and sedentary diabetic. These changes included: hepatocytes hypertrophy, presence and distribution of polysaccharides in the hepatocytes cytoplasm and, especially, congestion of the liver blood vessels.Conclusion: Our results suggest that aminoguanidine is not hepatotoxic, when used at dosage of 1 g/L for the treatment of diabetes complications, and confirmed that the practice of moderate physical exercise assuaged the damage caused by diabetes without the use of insulin. © 2013 e Nico et al.; licensee BioMed Central Ltd.

Morphometry and expression of MyoD and Myogenin in white and red skeletal muscles of juvenile fish Colossoma macropomum (Cuvier 1818)

Colossoma macropomum, also known as tambaqui, is an economically important fish species, and interesting new studies have been published with the aim of improving the growth of this fish. In this work, we describe the morphometric characteristics, as well as the mRNA and protein expression levels of two myogenic regulatory factors (MRFs)-myod/MyoD and myogenin/Myogenin-in the white and red muscle types of tambaqui. A high proportion of white and red muscle fibers with large diameters suggest a hypertrophic growth process in the skeletal muscle during juvenile stages. Comparisons between muscle types showed that, in red muscle, myogenin transcript levels were significantly higher than those of myod. In contrast, MyoD protein levels were significantly higher than those of Myogenin in red muscle. These results suggest that in red and white muscles of juvenile tambaqui, independent post-transcriptional mechanisms for regulating MyoD and Myogenin expression may exist, which could be differentially activated during muscle growth. Furthermore, these data also suggest that specific control mechanisms may regulate distinct muscle phenotypes. © 2013 The Royal Swedish Academy of Sciences.

Heart failure-induced skeletal myopathy in spontaneously hypertensive rats

Background: Although skeletal muscle atrophy and changes in myosin heavy chain (MyHC) isoforms have often been observed during heart failure, their pathophysiological mechanisms are not completely defined. In this study we tested the hypothesis that skeletal muscle phenotype changes are related to myogenic regulatory factors and myostatin/follistatin expression in spontaneously hypertensive rats (SHR) with heart failure. Methods: After developing tachypnea, SHR were subjected to transthoracic echocardiogram. Pathological evidence of heart failure was assessed during euthanasia. Age-matched Wistar-Kyoto (WKY) rats were used as controls. Soleus muscle morphometry was analyzed in histological sections, and MyHC isoforms evaluated by electrophoresis. Protein levels were assessed by Western blotting. Statistical analysis: Student's t test and Pearson correlation. Results: All SHR presented right ventricular hypertrophy and seven had pleuropericardial effusion. Echocardiographic evaluation showed dilation in the left chambers and left ventricular hypertrophy with systolic and diastolic dysfunction in SHR. Soleus weight and fiber cross sectional areas were lower (WKY 3615±412; SHR 2035±224 μm2; P < 0.001), and collagen fractional volume was higher in SHR. The relative amount of type I MyHC isoform was increased in SHR. Myogenin, myostatin, and follistatin expression was lower and MRF4 levels higher in SHR. Myogenin and follistatin expression positively correlated with fiber cross sectional areas and MRF4 levels positively correlated with I MyHC isoform. Conclusion: Reduced myogenin and follistatin expression seems to participate in muscle atrophy while increased MRF4 protein levels can modulate myosin heavy chain isoform shift in skeletal muscle of spontaneously hypertensive rats with heart failure. © 2012 Elsevier B.V.