RESUMO
Large animal models of heart failure play an essential role in the development of new therapeutic interventions due to their size and physiological similarities to humans. Efforts have been dedicated to creating a model of pressure-overload induced heart failure, and ascending aortic banding while still supra-coronary and not a perfect mimic of aortic stenosis in humans, closely resembling the human condition. The purpose of this study is to demonstrate a minimally invasive approach to induce left ventricular pressure overload by placing an aortic band, precisely calibrated with percutaneously introduced high-fidelity pressure sensors. This method represents a refinement of the surgical procedure (3Rs), resulting in homogenous trans-stenotic gradients and reduced intragroup variability. Additionally, it enables swift and uneventful animal recovery, leading to minimal mortality rates. Throughout the study, animals were followed for up to 2 months after surgery, employing transthoracic echocardiography and pressure-volume loop analysis. However, longer follow-up periods can be achieved if desired. This large animal model proves valuable for testing new drugs, particularly those targeting hypertrophy and the structural and functional alterations associated with left ventricular pressure overload.
Assuntos
Estenose da Valva Aórtica , Insuficiência Cardíaca , Humanos , Animais , Suínos , Coração , Insuficiência Cardíaca/etiologia , Estenose da Valva Aórtica/cirurgia , Ecocardiografia , Aorta/cirurgia , Hipertrofia Ventricular Esquerda , Modelos Animais de DoençasRESUMO
While it is experimentally supported that impaired myocardial vascularization contributes to a mismatch between myocardial oxygen demand and supply, a mechanistic basis for disruption of coordinated tissue growth and angiogenesis in heart failure remains poorly understood. Silencing strategies that impair microRNA biogenesis have firmly implicated microRNAs in the regulation of angiogenesis, and individual microRNAs prove to be crucial in developmental or tumor angiogenesis. A high-throughput functional screening for the analysis of a whole-genome microRNA silencing library with regard to their phenotypic effect on endothelial cell proliferation as a key parameter, revealed several anti- and pro-proliferative microRNAs. Among those was miR-216a, a pro-angiogenic microRNA which is enriched in cardiac microvascular endothelial cells and reduced in expression under cardiac stress conditions. miR-216a null mice display dramatic cardiac phenotypes related to impaired myocardial vascularization and unbalanced autophagy and inflammation, supporting a model where microRNA regulation of microvascularization impacts the cardiac response to stress.
Assuntos
Insuficiência Cardíaca , MicroRNAs , Animais , Camundongos , Células Endoteliais/metabolismo , Insuficiência Cardíaca/metabolismo , MicroRNAs/metabolismo , Miocárdio/metabolismo , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Fisiológica/genéticaRESUMO
[Figure: see text].
Assuntos
Potenciais de Ação , Bloqueio Atrioventricular/metabolismo , Nó Atrioventricular/metabolismo , Canais de Cálcio Tipo L/metabolismo , Frequência Cardíaca , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Miócitos Cardíacos/metabolismo , Resistência Física , Animais , Bloqueio Atrioventricular/induzido quimicamente , Bloqueio Atrioventricular/diagnóstico , Bloqueio Atrioventricular/fisiopatologia , Nó Atrioventricular/fisiopatologia , Atropina , Biópsia , Canais de Cálcio Tipo L/genética , Modelos Animais de Doenças , Eletrocardiografia , Cavalos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Condicionamento Físico Animal , Propranolol , Natação , Transcrição GênicaRESUMO
Obesity leads to an amplified risk of disease and contributes to the occurrence of type 2 diabetes, fatty liver disease, coronary heart disease, stroke, chronic kidney disease and various types of cancer. MicroRNAs (miRNAs), small non-coding RNA molecules of 20-25 nucleotides, can remain stable in plasma and have been studied as potential (predictive) biomarkers for obesity and related metabolic disorders. The aim of this study was to identify circulating miRNAs as biomarkers for obesity status and metabolic alterations in women. Circulating miR-216a and miR-155-5p were selected by miRNA expression profiling and validated by real time quantitative PCR in a validation cohort of 60 obese women and 60 normal weight-age-matched control women. This was supplemented by correlation analysis of the candidate miRNA and anthropometric variables, blood biochemistry and lipid profile markers. Circulating miR-216a was validated as a biomarker of obesity status with significantly reduced levels in obese women. Interestingly, this was associated with a negative correlation between the plasma miR-216a content and body mass index (BMI), waist circumference, mean arterial pressure (MAP), triglycerides, ratio of total cholesterol/high density lipoprotein (HDL)-cholesterol and high sensitivity-C reactive protein (hs-CRP).Taken together, we provide evidence for an abnormally expressed circulating miRNA, miR-216a, with additive value as a predictive marker for obesity that correlates with metabolic alterations presented by lipid profile and inflammatory markers.
RESUMO
Heart failure is preceded by ventricular remodeling, changes in left ventricular mass, and myocardial volume after alterations in loading conditions. Concentric hypertrophy arises after pressure overload, involves wall thickening, and forms a substrate for diastolic dysfunction. Eccentric hypertrophy develops in volume overload conditions and leads wall thinning, chamber dilation, and reduced ejection fraction. The molecular events underlying these distinct forms of cardiac remodeling are poorly understood. Here, we demonstrate that miR-148a expression changes dynamically in distinct subtypes of heart failure: while it is elevated in concentric hypertrophy, it decreased in dilated cardiomyopathy. In line, antagomir-mediated silencing of miR-148a caused wall thinning, chamber dilation, increased left ventricle volume, and reduced ejection fraction. Additionally, adeno-associated viral delivery of miR-148a protected the mouse heart from pressure-overload-induced systolic dysfunction by preventing the transition of concentric hypertrophic remodeling toward dilation. Mechanistically, miR-148a targets the cytokine co-receptor glycoprotein 130 (gp130) and connects cardiomyocyte responsiveness to extracellular cytokines by modulating the Stat3 signaling. These findings show the ability of miR-148a to prevent the transition of pressure-overload induced concentric hypertrophic remodeling toward eccentric hypertrophy and dilated cardiomyopathy and provide evidence for the existence of separate molecular programs inducing distinct forms of myocardial remodeling.
Assuntos
Cardiomiopatias/metabolismo , Insuficiência Cardíaca/metabolismo , Transplante de Coração/métodos , MicroRNAs/metabolismo , Miocárdio/metabolismo , Animais , Cardiomiopatias/genética , Proliferação de Células/fisiologia , Insuficiência Cardíaca/genética , Humanos , Camundongos , MicroRNAs/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/fisiologia , Remodelação Ventricular/genética , Remodelação Ventricular/fisiologiaRESUMO
Early and specific diagnosis of oxidative stress linked diseases as cardiac heart diseases remains a major dilemma for researchers and clinicians. MicroRNAs may serve as a better tool for specific early diagnostics and propose their utilization in future molecular medicines. We aimed to measure the microRNAs expressions in oxidative stress linked cardiac hypertrophic condition induced through stimulants as Endothelin and Isoproterenol. Cardiac hypertrophic animal models were confirmed by BNP, GATA4 expression, histological assays, and increased cell surface area. High oxidative stress (ROS level) and decreased antioxidant activities were assessed in hypertrophied groups. Enhanced expression of miR-152, miR-212/132 while decreased miR-142-3p expression was observed in hypertrophic condition. Similar pattern of these microRNAs was detected in HL-1â¯cells treated with H2O2. Upon administration of antioxidants, the miRNAs expression pattern altered from that of the cardiac hypertrophied model. Present investigation suggests that oxidative stress generated during the cardiac pathology may directly or indirectly regulate anti-hypertrophy pathway elements through microRNAs including antioxidant enzymes, which need further investigation. The down-regulation of free radical scavengers make it easier for the oxidative stress to play a key role in disease progression.