RESUMO
Diabetes mellitus is one of the leading causes of chronic kidney disease and its progression to end-stage kidney disease (ESKD). Diabetic kidney disease (DKD) is characterized by glomerular hypertrophy, hyperfiltration, inflammation, and the onset of albuminuria, together with a progressive reduction in glomerular filtration rate. This progression is further accompanied by tubulointerstitial inflammation and fibrosis. Factors such as genetic predisposition, epigenetic modifications, metabolic derangements, hemodynamic alterations, inflammation, and inappropriate renin-angiotensin-aldosterone system (RAAS) activity contribute to the onset and progression of DKD. In this context, decades of work have focused on glycemic and blood pressure reduction strategies, especially targeting the RAAS to slow disease progression. Although much of the work has focused on targeting angiotensin II, emerging data support that the mineralocorticoid receptor (MR) is integral in the development and progression of DKD. Molecular mechanisms linked to the underlying pathophysiological changes derived from MR activation include vascular endothelial and epithelial cell responses to oxidative stress and inflammation. These responses lead to alterations in the microcirculatory environment, the abnormal release of extracellular vesicles, gut dysbiosis, epithelial-mesenchymal transition, and kidney fibrosis. Herein, we present recent experimental and clinical evidence on the MR in DKD onset and progress along with new MR-based strategies for the treatment and prevention of DKD.
Assuntos
Nefropatias Diabéticas , Receptores de Mineralocorticoides , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/fisiopatologia , Humanos , Receptores de Mineralocorticoides/metabolismo , Animais , Sistema Renina-Angiotensina , Rim/metabolismo , Rim/patologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Transdução de Sinais , Progressão da DoençaRESUMO
Consumption of a Western diet (WD) increases CD36 expression in vascular, hepatic, and skeletal muscle tissues promoting lipid metabolic disorders and insulin resistance. We further examined the role of endothelial cell specific CD36 (ECCD36) signaling in contributing to skeletal muscle lipid metabolic disorders, insulin resistance, and their underlying molecular mechanisms. Female ECCD36 wild type (ECCD36+/+) and knock out (ECCD36-/-) mice, aged six weeks, were provided with either a WD or a standard chow diet for a duration of 16 weeks. ECCD36+/+ WD mice were characterized by elevated fasting plasma glucose and insulin levels, increased homeostatic model assessment for insulin resistance, and glucose intolerance that were blunted in ECCD36-/- mice. Improved insulin sensitivity in ECCD36-/- mice was characterized by increased phosphoinositide 3-kinases/protein kinase B signaling that further augmented glucose transporter type 4 expression and glucose uptake. Meanwhile, 16 weeks of WD feeding also increased skeletal muscle free fatty acid (FFA) and lipid accumulation, without any observed changes in plasma FFA levels. These lipid metabolic disorders were blunted in ECCD36-/- mice. Moreover, ECCD36 also mediated in vitro palmitic acid-induced lipid accumulation in cultured ECs, subsequently leading to the release of FFAs into the culture media. Furthermore, consumption of a WD increased FFA oxidation, mitochondrial dysfunction, impaired mitochondrial respiratory, skeletal muscle fiber type transition, and fibrosis. These WD-induced abnormalities were blunted in ECCD36-/- mice. These findings demonstrate that endothelial specific ECCD36 signaling participates in skeletal muscle FFA uptake, ectopic lipid accumulation, mitochondrial dysfunction, insulin resistance, and associated skeletal muscle dysfunction in diet-induced obesity.
RESUMO
Duchenne muscular dystrophy (DMD) is characterized by severe degeneration and necrosis of both skeletal and cardiac muscle. While many experimental therapies have shown great promise in treating skeletal muscle disease, an effective therapy for Duchenne cardiomyopathy remains a challenge in large animal models and human patients. The current views on cardiac consequences of skeletal muscle-centered therapy are controversial. Studies performed in young adult mdx mice (a mild DMD mouse model) have yielded opposing results. Since mdx mice do not develop dystrophic cardiomyopathy until ≥21 months of age, we reasoned that old mdx mice may represent a better model to assess the impact of skeletal muscle rescue on dystrophic heart disease. Here, we aged skeletal muscle-specific micro-dystrophin transgenic mdx mice to 23 months and examined the cardiac phenotype. As expected, transgenic mdx mice had minimal skeletal muscle disease and they also outperformed original mdx mice on treadmill running. On cardiac examination, the dystrophin-null heart of transgenic mdx mice displayed severe cardiomyopathy matching that of non-transgenic mdx mice. Specifically, both the strains showed similar heart fibrosis and cardiac function deterioration in systole and diastole. Cardiac output and ejection fraction were also equally compromised. Our results suggest that skeletal muscle rescue neither aggravates nor alleviates cardiomyopathy in aged mdx mice. These findings underscore the importance of treating both skeletal and cardiac muscles in DMD therapy.
Assuntos
Cardiomiopatias/etiologia , Distrofia Muscular de Duchenne/complicações , Fatores Etários , Animais , Peso Corporal/genética , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Modelos Animais de Doenças , Distrofina/genética , Distrofina/metabolismo , Fibrose , Ventrículos do Coração/fisiopatologia , Masculino , Camundongos Endogâmicos mdx , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Tamanho do Órgão/genéticaRESUMO
Overnutrition/obesity predisposes individuals, particularly women, to diastolic dysfunction (DD), an independent predictor of future cardiovascular disease. We examined whether low-dose spironolactone (Sp) prevents DD associated with consumption of a Western Diet (WD) high in fat, fructose, and sucrose. Female C57BL6J mice were fed a WD with or without Sp (1 mg·kg(-1)·day(-1)). After 4 mo on the WD, mice exhibited increased body weight and visceral fat, but similar blood pressures, compared with control diet-fed mice. Sp prevented the development of WD-induced DD, as indicated by decreased isovolumic relaxation time and an improvement in myocardial performance (Assuntos
Diástole/efeitos dos fármacos
, Dieta Ocidental
, Ventrículos do Coração/efeitos dos fármacos
, Antagonistas de Receptores de Mineralocorticoides/administração & dosagem
, Receptores de Mineralocorticoides/efeitos dos fármacos
, Espironolactona/administração & dosagem
, Disfunção Ventricular Esquerda/prevenção & controle
, Função Ventricular Esquerda/efeitos dos fármacos
, Animais
, Cardiomegalia/patologia
, Cardiomegalia/fisiopatologia
, Cardiomegalia/prevenção & controle
, Dieta Hiperlipídica
, Sacarose Alimentar
, Modelos Animais de Doenças
, Feminino
, Fibrose
, Frutose
, Ventrículos do Coração/imunologia
, Ventrículos do Coração/metabolismo
, Ventrículos do Coração/patologia
, Ventrículos do Coração/fisiopatologia
, Mediadores da Inflamação/metabolismo
, Camundongos Endogâmicos C57BL
, Miócitos Cardíacos/efeitos dos fármacos
, Miócitos Cardíacos/metabolismo
, Estresse Oxidativo/efeitos dos fármacos
, Receptores de Mineralocorticoides/metabolismo
, Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo
, Sarcômeros/efeitos dos fármacos
, Sarcômeros/metabolismo
, Fatores Sexuais
, Fatores de Tempo
, Disfunção Ventricular Esquerda/etiologia
, Disfunção Ventricular Esquerda/imunologia
, Disfunção Ventricular Esquerda/metabolismo
, Disfunção Ventricular Esquerda/patologia
, Disfunção Ventricular Esquerda/fisiopatologia
, Pressão Ventricular/efeitos dos fármacos
, Remodelação Ventricular/efeitos dos fármacos
RESUMO
Duchenne muscular dystrophy (DMD) is a fatal genetic disease caused by the absence of the sarcolemmal protein dystrophin. Dilated cardiomyopathy leading to heart failure is a significant source of morbidity and mortality in DMD. We recently demonstrated amelioration of DMD heart disease in 16 to 20-m-old dystrophin-null mdx mice using adeno-associated virus (AAV) mediated micro-dystrophin gene therapy. DMD patients show severe heart disease near the end of their life expectancy. Similarly, mdx mice exhibit profoundly worsening heart disease when they reach beyond 21 months of age. To more rigorously test micro-dystrophin therapy, we treated mdx mice that were between 21.2 and 22.7-m-old (average, 22.1 ± 0.2 months; N=8). The ∆R4-23/∆C micro-dystrophin gene was packaged in the cardiotropic AAV-9 virus. 5×10(12) viral genome particles/mouse were delivered to mdx mice via the tail vein. AAV transduction, myocardial fibrosis and heart function were examined 1.7 ± 0.2 months after gene therapy. Efficient micro-dystrophin expression was observed in the myocardium of treated mice. Despite the robust dystrophin expression, myocardial fibrosis was not mitigated. Most hemodynamic parameters were not improved either. However, ECG abnormalities were partially corrected. Importantly, treated mice became more resistant to dobutamine-induced cardiac death. In summary, we have revealed for the first time the potential benefits and limitations of AAV micro-dystrophin therapy in end-stage Duchenne dilated cardiomyopathy. Our findings have important implications for the use of AAV gene therapy in dilated cardiomyopathy and heart failure.
Assuntos
Cardiomiopatias/metabolismo , Cardiomiopatias/terapia , Distrofina/fisiologia , Fibrose Endomiocárdica/metabolismo , Fibrose Endomiocárdica/terapia , Terapia Genética/métodos , Animais , Dependovirus/genética , Distrofina/genética , Feminino , Camundongos , Camundongos Endogâmicos mdx , Distrofia Muscular Animal/metabolismo , Distrofia Muscular Animal/terapia , Distrofia Muscular de Duchenne/metabolismoRESUMO
Dystrophin deficiency leads to lethal dilated Duchenne cardiomyopathy. A promising therapy is to deliver a highly abbreviated microdystrophin gene to the heart using adeno-associated virus (AAV). Microdystrophin has been shown to mitigate dystrophin-deficient skeletal muscle disease. However, it is not clear whether microdystrophin is equally effective in treating Duchenne cardiomyopathy. To evaluate microdystrophin therapy in the heart, we injected 5 × 10(12) viral genome particles/mouse of AAV-9 ΔR4-23/ΔC microdystrophin vector via tail vein to ~16-20-month-old (average 18.7-month-old) female mdx mice, a manifesting model of Duchenne cardiomyopathy. Cardiac transduction and heart function were examined at 2-8 months after gene transfer. We observed robust myocardial microdystrophin expression. Electrocardiography (ECG) and left ventricular catheter hemodynamic assays also revealed significant improvement. Furthermore, AAV-microdystrophin therapy prevented dobutamine-stress induced acute cardiac death. We demonstrate for the first time that AAV microdystrophin therapy significantly ameliorates functional deficiency in a phenotypic model of Duchenne cardiomyopathy. Our results support further exploration of microdystrophin therapy to treat Duchenne cardiomyopathy.
Assuntos
Envelhecimento/fisiologia , Dependovirus/genética , Distrofina/uso terapêutico , Testes de Função Cardíaca , Animais , Dobutamina/efeitos adversos , Distrofina/genética , Eletrocardiografia , Feminino , Vetores Genéticos , Hemodinâmica , Camundongos , Camundongos Endogâmicos mdx , Transdução GenéticaRESUMO
BACKGROUND: Cardiomyocyte calcium overloading has been implicated in the pathogenesis of Duchenne muscular dystrophy (DMD) heart disease. The cardiac isoform of sarcoplasmic reticulum calcium ATPase (SERCA2a) plays a major role in removing cytosolic calcium during heart muscle relaxation. Here, we tested the hypothesis that SERCA2a over-expression may mitigate electrocardiography (ECG) abnormalities in old female mdx mice, a murine model of DMD cardiomyopathy. METHODS: 1 × 10(12) viral genome particles/mouse of adeno-associated virus serotype-9 (AAV-9) SERCA2a vector was delivered to 12-m-old female mdx mice (N = 5) via a single bolus tail vein injection. AAV transduction and the ECG profile were examined eight months later. RESULTS: The vector genome was detected in the hearts of all AAV-injected mdx mice. Immunofluorescence staining and western blot confirmed SERCA2a over-expression in the mdx heart. Untreated mdx mice showed characteristic tachycardia, PR interval reduction and QT interval prolongation. AAV-9 SERCA2a treatment corrected these ECG abnormalities. CONCLUSIONS: Our results suggest that AAV SERCA2a therapy may hold great promise in treating dystrophin-deficient heart disease.
Assuntos
Envelhecimento/patologia , Eletrocardiografia , Técnicas de Transferência de Genes , Terapia Genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/uso terapêutico , Animais , Dependovirus/genética , Feminino , Vetores Genéticos/genética , Humanos , Camundongos , Camundongos Endogâmicos mdx , Miocárdio/metabolismo , Miocárdio/patologia , Transdução GenéticaRESUMO
BACKGROUND Filamin C (FLNC) is an actin crosslinking protein that provides structural support for the sarcomere. The exact function of FLNC is unknown; however, mutations have been reported in myopathies and cardiomyopathies, but rarely both. In this paper, we describe a case of adult-onset camptocormia, proximal myopathy, and cardiomyopathy and an intronic FLNC mutation. CASE REPORT A 56-year-old man was referred to the neurology clinic for truncal weakness. The patient reported having curvature of his spine, which he said his mother also had prior to her dying suddenly due to a "cardiac issue." The patient was found to have fatty infiltration of the periscapular and paraspinal muscles. Additionally, electromyography revealed irritable myopathy of the paraspinal muscles, and an echocardiogram revealed an ejection fraction of 40%. A genetic panel conducted through PerkinElmer Genomics revealed a heterozygous mutation c.1210+3A>G in the intron region of FLNC. Due to his low ejection fraction and family history of sudden cardiac death, he received an implantable cardioverter-defibrillator and began carvedilol. The patient received physical therapy for camptocormia. CONCLUSIONS The variability in genotypic-phenotypic relationships of FLNC mutations is a growing area of research. It is important to increase awareness to further the development of gene-targeted therapies. We hope this unique clinical presentation of co-occurring skeletal and cardiomyopathy secondary to an intronic mutation will increase awareness of the broad phenotypic spectrum of FLNC mutations.
Assuntos
Cardiomiopatias , Doenças Musculares , Adulto , Feminino , Filaminas/genética , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia Muscular Espinal , Mutação , Curvaturas da Coluna VertebralRESUMO
Aged mdx mice represent an important model for studying Duchenne cardiomyopathy. Herein we compared the cardiac phenotypes of 22-month-old male and female mdx mice. Surprisingly, only females displayed the characteristic cardiac dilation on pressure-volume loop analysis. Female mdx mice also exhibited lower contractility, larger Q waves, and higher ratios of heart weight to body weight. Our results reveal significant gender disparity in mdx cardiac function. Gender should be considered when using the mdx model for the study of Duchenne cardiomyopathy.
Assuntos
Cardiomiopatia Dilatada/etiologia , Cardiomiopatia Dilatada/fisiopatologia , Coração/fisiopatologia , Camundongos Endogâmicos mdx , Distrofia Muscular de Duchenne/complicações , Fatores Sexuais , Animais , Pressão Sanguínea , Volume Sanguíneo , Cardiomiopatia Dilatada/patologia , Eletrocardiografia , Feminino , Fibrose , Hemodinâmica , Hidroxiprolina/análise , Masculino , Camundongos , Contração Miocárdica , Miocárdio/química , Miocárdio/patologia , FenótipoRESUMO
A cure for dystrophin-deficient muscular dystrophy requires treating both skeletal muscle and the heart. Whereas mosaic dystrophin expression has been shown to protect skeletal muscle, controversy exists over whether mosaic expression is protective in the heart. We have shown recently that mosaic dystrophin expression prevents stress-induced heart damage in young carrier mice. Although an interesting finding, the clinical relevance remains to be established because young dystrophin-null mdx mice do not have heart disease. On the other hand, heart failure has been reported in human carriers. To resolve this mouse/human discrepancy, we evaluated the cardiac phenotype in 21-month-old mdx, carrier, and normal mice. We found dilated cardiomyopathy in old mdx mice but not in age-matched carrier mice. All anatomical parameters and physiological assay results (ECG and closed-chest Millar catheter) were within the normal range in old carrier mice. Focal myocardial inflammation was found in a small fraction of old carrier mice, but it had no major impact on heart function. Dobutamine stress revealed a near normal hemodynamic profile except for a marginal reduction in systolic pressure in old carrier mice. Immunostaining and Western blot showed dystrophin expression in 50% cardiomyocytes in old carrier mice. Interestingly, utrophin was upregulated in dystrophin-negative heart cells in carrier mice. In summary, we have provided the first clear-cut evidence that dilated cardiomyopathy in old mdx mice was prevented by mosaic dystrophin expression or complementary dystrophin/utrophin expression. Our results raise the hope for ameliorating dystrophic cardiomyopathy through partial gene and/or cell therapy.
Assuntos
Cardiomiopatias/prevenção & controle , Distrofina/deficiência , Utrofina/genética , Fatores Etários , Animais , Cardiomiopatias/genética , Cardiomiopatia Dilatada/genética , DNA Complementar , Distrofina/genética , Expressão Gênica , Heterozigoto , Camundongos , Camundongos Knockout , MosaicismoRESUMO
Duchenne muscular dystrophy (DMD) affects both skeletal and cardiac muscle. It is currently unclear whether the strategies developed for skeletal muscle can ameliorate cardiomyopathy. Synthetic mini-/micro-dystrophin genes have yielded impressive skeletal muscle protection in animal models. The 6-kb DeltaH2-R19 minigene is particularly promising because it completely restores skeletal muscle force to wild-type levels. Here, we examined whether expressing this minigene in the heart, but not skeletal muscle, could normalize cardiac function in the mdx model of DMD cardiomyopathy. Transgenic mdx mice were generated to express the DeltaH2-R19 minigene under the control of the alpha-myosin heavy-chain promoter. Heart structure and function were examined in adult and very old mice. The DeltaH2-R19 minigene enhanced cardiomyocyte sarcolemmal strength and prevented myocardial fibrosis. It also restored the dobutamine response and enhanced treadmill performance. Surprisingly, heart-restricted DeltaH2-R19 minigene expression did not completely normalize electrocardiogram and hemodynamic abnormalities. Overall, systolic function and ejection fraction were restored to normal levels but stroke volume and cardiac output remained suboptimal. Our results demonstrate that the skeletal muscle-proven DeltaH2-R19 minigene can correct cardiac histopathology but cannot fully normalize heart function. Novel strategies must be developed to completely restore heart function in DMD.
Assuntos
Distrofina/metabolismo , Distrofina/fisiologia , Coração/fisiologia , Músculo Esquelético/metabolismo , Distrofia Muscular Animal/terapia , Miocárdio/metabolismo , Animais , Southern Blotting , Western Blotting , Distrofina/genética , Imunofluorescência , Camundongos , Camundongos Endogâmicos mdx , Camundongos Transgênicos , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Distrofia Muscular Animal/genética , Miocárdio/patologia , Reação em Cadeia da PolimeraseRESUMO
OBJECTIVE: Obesity is associated with myocardial fibrosis and impaired diastolic relaxation, abnormalities that are especially prevalent in women. Normal coronary vascular endothelial function is integral in mediating diastolic relaxation, and recent work suggests increased activation of the endothelial cell (EC) mineralocorticoid receptor (ECMR) is associated with impaired diastolic relaxation. As the endothelial Na+ channel (EnNaC) is a downstream target of the ECMR, we sought to determine whether EC-specific deletion of the critical alpha subunit, αEnNaC, would prevent diet induced-impairment of diastolic relaxation in female mice. METHODS AND MATERIALS: Female αEnNaC KO mice and littermate controls were fed a Western diet (WD) high in fat (46%), fructose corn syrup (17.5%) and sucrose (17.5%) for 12-16â¯weeks. Measurements were conducted for in vivo cardiac function, in vitro cardiomyocyte stiffness and EnNaC activity in primary cultured ECs. Additional biochemical studies examined indicators of oxidative stress, including aspects of antioxidant Nrf2 signaling, in cardiac tissue. RESULTS: Deletion of αEnNaC in female mice fed a WD significantly attenuated WD mediated impairment in diastolic relaxation. Improved cardiac relaxation was accompanied by decreased EnNaC-mediated Na+ currents in ECs and reduced myocardial oxidative stress. Further, deletion of αEnNaC prevented WD-mediated increases in isolated cardiomyocyte stiffness. CONCLUSION: Collectively, these findings support the notion that WD feeding in female mice promotes activation of EnNaC in the vasculature leading to increased cardiomyocyte stiffness and diastolic dysfunction.
Assuntos
Diástole/efeitos dos fármacos , Dieta Ocidental/efeitos adversos , Células Endoteliais/química , Coração/fisiopatologia , Canais de Sódio/metabolismo , Rigidez Vascular/efeitos dos fármacos , Animais , Células Cultivadas , Células Endoteliais/metabolismo , Feminino , Camundongos , Camundongos Knockout , Miócitos Cardíacos/patologia , Estresse Oxidativo , Canais de Sódio/deficiênciaRESUMO
The success of many gene therapy applications hinges on efficient whole body transduction. In the case of muscular dystrophies, a therapeutic vector has to reach every muscle in the body. Recent studies suggest that vectors based on adeno-associated virus (AAV) are capable of body-wide transduction in rodents. However, translating this finding to large animals remains a challenge. Here we explored systemic gene delivery with AAV serotype-9 (AAV-9) in neonatal dogs. Previous attempts to directly deliver AAV to adult canine muscle have yielded minimal transduction due to a strong cellular immune response. However, in neonatal dogs we observed robust skeletal muscle transduction throughout the body after a single intravenous injection. Importantly, systemic transduction was achieved in the absence of pharmacological intervention or immune suppression and it lasted for at least 6 months (the duration of study). We also observed several unique features not predicted by murine studies. In particular, cardiac muscle was barely transduced in dogs. Many muscular dystrophy patients can be identified by neonatal screening. The technology described here may lead to an effective early intervention in these patients.
Assuntos
Dependovirus/genética , Músculo Esquelético/metabolismo , Transgenes/genética , Animais , Animais Recém-Nascidos , Dependovirus/imunologia , Cães , Vetores Genéticos/genética , Injeções Intravenosas , Microcirculação , Músculo Esquelético/imunologiaRESUMO
Obesity is known to be a strong predictor of sudden cardiac death. For this reason, concern exists that this association may be related to delayed ventricular repolarization (VR), which has been extensively studied in overweight and obese patients. The corrected QT interval (QTc) and QT or QTc dispersion have been the most commonly-used electrocardiographic methods for assessing VR. Multiple controlled studies demonstrated that QTc and QT or QTc dispersion were significantly longer/greater in overweight and obese subjects than in normal weight controls. The preponderance of evidence indicates that weight loss in overweight and obese patients, whether achieved by diet or bariatric surgery, significantly shortens QTc and decreases QT or QTc dispersion. Several co-morbidities that are commonly associated with obesity may delay VR. These include diabetes mellitus, the metabolic syndrome, systemic hypertension, left ventricular hypertrophy, heart failure, and obstructive sleep apnea. It is unclear whether overweight and obesity are independent predictors of delayed VR. It is also uncertain whether prolongation of QTc in such patients is sufficient to predispose to potentially fatal ventricular arrhythmias.
Assuntos
Arritmias Cardíacas/fisiopatologia , Ventrículos do Coração/fisiopatologia , Obesidade/fisiopatologia , Função Ventricular Esquerda , Potenciais de Ação , Adiposidade , Adolescente , Adulto , Fatores Etários , Arritmias Cardíacas/epidemiologia , Arritmias Cardíacas/prevenção & controle , Criança , Comorbidade , Metabolismo Energético , Feminino , Frequência Cardíaca , Humanos , Masculino , Obesidade/epidemiologia , Obesidade/terapia , Obesidade Infantil/epidemiologia , Obesidade Infantil/fisiopatologia , Obesidade Infantil/terapia , Prognóstico , Fatores de Proteção , Fatores de Risco , Fatores Sexuais , Redução de Peso , Adulto JovemRESUMO
OBJECTIVE: Obesity is a global epidemic with profound cardiovascular disease (CVD) complications. Obese women are particularly vulnerable to CVD, suffering higher rates of CVD compared to non-obese females. Diastolic dysfunction is the earliest manifestation of CVD in obese women but remains poorly understood with no evidence-based therapies. We have shown early diastolic dysfunction in obesity is associated with oxidative stress and myocardial fibrosis. Recent evidence suggests exercise may increase levels of the antioxidant heme oxygenase-1 (HO-1). Accordingly, we hypothesized that diastolic dysfunction in female mice consuming a western diet (WD) could be prevented by daily volitional exercise with reductions in oxidative stress, myocardial fibrosis and maintenance of myocardial HO-1 levels. MATERIALS/METHODS: Four-week-old female C57BL/6J mice were fed a high-fat/high-fructose WD for 16weeks (N=8) alongside control diet fed mice (N=8). A separate cohort of WD fed females was allowed a running wheel for the entire study (N=7). Cardiac function was assessed at 20weeks by high-resolution cardiac magnetic resonance imaging (MRI). Functional assessment was followed by immunohistochemistry, transmission electron microscopy (TEM) and Western blotting to identify pathologic mechanisms and assess HO-1 protein levels. RESULTS: There was no significant body weight decrease in exercising mice, normalized body weight 14.3g/mm, compared to sedentary mice, normalized body weight 13.6g/mm (p=0.38). Total body fat was also unchanged in exercising, fat mass of 6.6g, compared to sedentary mice, fat mass 7.4g (p=0.55). Exercise prevented diastolic dysfunction with a significant reduction in left ventricular relaxation time to 23.8ms for exercising group compared to 33.0ms in sedentary group (p<0.01). Exercise markedly reduced oxidative stress and myocardial fibrosis with improved mitochondrial architecture. HO-1 protein levels were increased in the hearts of exercising mice compared to sedentary WD fed females. CONCLUSIONS: This study provides seminal evidence that exercise can prevent diastolic dysfunction in WD-induced obesity in females even without changes in body weight. Furthermore, the reduction in myocardial oxidative stress and fibrosis and improved HO-1 levels in exercising mice suggests a novel mechanism for the antioxidant effect of exercise.
Assuntos
Cardiomiopatias/prevenção & controle , Diástole , Heme Oxigenase-1/metabolismo , Miocárdio/metabolismo , Obesidade/terapia , Condicionamento Físico Animal/fisiologia , Animais , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Ritmo Circadiano , Dieta Ocidental , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Obesidade/patologia , Obesidade/fisiopatologia , Estresse OxidativoRESUMO
Dystrophin gene replacement holds the promise of treating Duchenne muscular dystrophy. Supraphysiological expression is a concern for all gene therapy studies. In the case of Duchenne muscular dystrophy, Chamberlain and colleagues found that 50-fold overexpression did not cause deleterious side effect in skeletal muscle. To determine whether excessive dystrophin expression in the heart is safe, we studied two lines of transgenic mdx mice that selectively expressed a therapeutic minidystrophin gene in the heart at 50-fold and 100-fold of the normal levels. In the line with 50-fold overexpression, minidystrophin showed sarcolemmal localization and electrocardiogram abnormalities were corrected. However, in the line with 100-fold overexpression, we not only detected sarcolemmal minidystrophin expression but also observed accumulation of minidystrophin vesicles in the sarcoplasm. Excessive minidystrophin expression did not correct tachycardia, a characteristic feature of Duchenne muscular dystrophy. Importantly, several electrocardiogram parameters (QT interval, QRS duration and the cardiomyopathy index) became worse than that of mdx mice. Our data suggests that the mouse heart can tolerate 50-fold minidystrophin overexpression, but 100-fold overexpression leads to cardiac toxicity.
RESUMO
Obesity produces a variety of hemodynamic alterations that may cause changes in cardiac morphology which predispose to left and right ventricular dysfunction. Various neurohormonal and metabolic alterations commonly associated with obesity may contribute to these abnormalities of cardiac structure and function. These changes in cardiovascular hemodynamics, cardiac morphology, and ventricular function may, in severely obese patients, predispose to heart failure, even in the absence of other forms of heart disease (obesity cardiomyopathy). In normotensive obese patients, cardiac involvement is commonly characterized by elevated cardiac output, low peripheral vascular resistance, and increased left ventricular (LV) end-diastolic pressure. Sleep-disordered breathing may lead to pulmonary arterial hypertension and, in association with left heart failure, may contribute to elevation of right heart pressures. These alterations, in association with various neurohormonal and metabolic abnormalities, may produce LV hypertrophy; impaired LV diastolic function; and less commonly, LV systolic dysfunction. Many of these alterations are reversible with substantial voluntary weight loss.
Assuntos
Sistema Cardiovascular/fisiopatologia , Coração/fisiopatologia , Hemodinâmica/fisiologia , Hipertensão/fisiopatologia , Miocárdio/patologia , Obesidade/fisiopatologia , Função Ventricular/fisiologia , Sistema Cardiovascular/patologia , Humanos , Hipertensão/etiologia , Hipertensão/patologia , Obesidade/complicações , Obesidade/patologia , Tamanho do Órgão/fisiologiaRESUMO
We recently showed that Western diet-induced obesity and insulin resistance promotes endothelial cortical stiffness in young female mice. Herein, we tested the hypothesis that regular aerobic exercise would attenuate the development of endothelial and whole artery stiffness in female Western diet-fed mice. Four-week-old C57BL/6 mice were randomized into sedentary (ie, caged confined, n=6) or regular exercise (ie, access to running wheels, n=7) conditions for 16 weeks. Exercise training improved glucose tolerance in the absence of changes in body weight and body composition. Compared with sedentary mice, exercise-trained mice exhibited reduced endothelial cortical stiffness in aortic explants (sedentary 11.9±1.7 kPa versus exercise 5.5±1.0 kPa; P<0.05), as assessed by atomic force microscopy. This effect of exercise was not accompanied by changes in aortic pulse wave velocity (P>0.05), an in vivo measure of aortic stiffness. In comparison, exercise reduced femoral artery stiffness in isolated pressurized arteries and led to an increase in femoral internal artery diameter and wall cross-sectional area (P<0.05), indicative of outward hypertrophic remodeling. These effects of exercise were associated with an increase in femoral artery elastin content and increased number of fenestrae in the internal elastic lamina (P<0.05). Collectively, these data demonstrate for the first time that the aortic endothelium is highly plastic and, thus, amenable to reductions in stiffness with regular aerobic exercise in the absence of changes in in vivo whole aortic stiffness. Comparatively, the same level of exercise caused destiffening effects in peripheral muscular arteries, such as the femoral artery, that perfuse the working limbs.
Assuntos
Dieta Ocidental/efeitos adversos , Artéria Femoral/patologia , Obesidade/prevenção & controle , Condicionamento Físico Animal/métodos , Comportamento Sedentário , Rigidez Vascular/fisiologia , Animais , Doenças Cardiovasculares/prevenção & controle , Modelos Animais de Doenças , Endotélio Vascular/patologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Valores de ReferênciaRESUMO
The rising obesity rates parallel increased consumption of a Western diet, high in fat and fructose, which is associated with increased uric acid. Population-based data support that elevated serum uric acids are associated with left ventricular hypertrophy and diastolic dysfunction. However, the mechanism by which excess uric acid promotes these maladaptive cardiac effects has not been explored. In assessing the role of Western diet-induced increases in uric acid, we hypothesized that reductions in uric acid would prevent Western diet-induced development of cardiomyocyte hypertrophy, cardiac stiffness, and impaired diastolic relaxation by reducing growth and profibrotic signaling pathways. Four-weeks-old C57BL6/J male mice were fed excess fat (46%) and fructose (17.5%) with or without allopurinol (125 mg/L), a xanthine oxidase inhibitor, for 16 weeks. The Western diet-induced increases in serum uric acid along with increases in cardiac tissue xanthine oxidase activity temporally related to increases in body weight, fat mass, and insulin resistance without changes in blood pressure. The Western diet induced cardiomyocte hypertrophy, myocardial oxidative stress, interstitial fibrosis, and impaired diastolic relaxation. Further, the Western diet enhanced activation of the S6 kinase-1 growth pathway and the profibrotic transforming growth factor-ß1/Smad2/3 signaling pathway and macrophage proinflammatory polarization. All results improved with allopurinol treatment, which lowered cardiac xanthine oxidase as well as serum uric acid levels. These findings support the notion that increased production of uric acid with intake of a Western diet promotes cardiomyocyte hypertrophy, inflammation, and oxidative stress that lead to myocardial fibrosis and associated impaired diastolic relaxation.