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Cardiac fibroblasts play a pivotal role in maintaining heart homeostasis by depositing extracellular matrix (ECM) to provide structural support for the myocardium, vasculature, and neuronal network and by contributing to essential physiological processes. In response to injury such as myocardial infarction or pressure overload, fibroblasts become activated, leading to increased ECM production that can ultimately drive left ventricular remodeling and progress to heart failure. Recently, the AJP-Heart and Circulatory Physiology issued a call for papers on cardiac fibroblasts that yielded articles with topics spanning fibroblast physiology, technical considerations, signaling pathways, and interactions with other cell types. This mini-review summarizes those articles and places the new findings in the context of what is currently known for cardiac fibroblasts and what future directions remain.
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Due to its ability to induce heterogenous, patient-specific damage in pulmonary alveoli and capillaries, COVID-19 poses challenges in defining a uniform profile to elucidate infection across all patients. Computational models that integrate changes in ventilation and perfusion with heterogeneous damage profiles offer valuable insights into the impact of COVID-19 on pulmonary health. This study aims to develop an in silico hypothesis-testing platform specifically focused on studying microvascular pulmonary perfusion in COVID-19-infected lungs. Through this platform, we explore the effects of various acinar-level pulmonary perfusion abnormalities on global lung function. Our modelling approach simulates changes in pulmonary perfusion and the resulting mismatch of ventilation and perfusion in COVID-19-afflicted lungs. Using this coupled modelling platform, we conducted multiple simulations to assess different scenarios of perfusion abnormalities in COVID-19-infected lungs. The simulation results showed an overall decrease in ventilation-perfusion (V/Q) ratio with inclusion of various types of perfusion abnormalities such as hypoperfusion with and without microangiopathy. This model serves as a foundation for comprehending and comparing the spectrum of findings associated with COVID-19 in the lung, paving the way for patient-specific modelling of microscale lung damage in emerging pulmonary pathologies like COVID-19.
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COVID-19 , Simulación por Computador , Pulmón , COVID-19/fisiopatología , Humanos , Pulmón/irrigación sanguínea , Pulmón/fisiopatología , Modelos Biológicos , Circulación Pulmonar , Microvasos/fisiopatologíaRESUMEN
Antibodies are one of the most used reagents in scientific laboratories and are critical components for a multitude of experiments in physiology research. Over the past decade, concerns about many biological methods, including those that use antibodies, have arisen as several laboratories were unable to reproduce the scientific data obtained in other laboratories. The lack of reproducibility could be largely attributed to inadequate reporting of detailed methods, no or limited verification by authors, and the production and use of unvalidated antibodies. The goal of this guideline article is to review best practices concerning commonly used techniques involving antibodies, including immunoblotting, immunohistochemistry, and flow cytometry. Awareness and integration of best practices will increase the rigor and reproducibility of these techniques and elevate the quality of physiology research.
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Anticuerpos , Reproducibilidad de los Resultados , Inmunohistoquímica , Citometría de Flujo , Especificidad de AnticuerposRESUMEN
Cardiovascular disease (CVD) is a serious health burden with increasing prevalence, and CVD continues to be the principal global source of illness and mortality. For several disorders, including CVD, the use of dietary and medicinal herbs instead of pharmaceutical drugs continues to be an alternate therapy strategy. Despite the prevalent use of synthetic pharmaceutical medications, there is currently an unprecedented push for the use of diet and herbal preparations in contemporary medical systems. This urge is fueled by a number of factors, the two most important being the common perception that they are safe and more cost-effective than modern pharmaceutical medicines. However, there is a lack of research focused on novel treatment targets that combine all these strategies-pharmaceuticals, diet, and herbs. In this review, we looked at the reported effects of pharmaceutical drugs and diet, as well as medicinal herbs, and propose a combination of these approaches to target independent pathways that could synergistically be efficacious in treating cardiovascular disease.
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AIMS: A peptide mimetic of a collagen-derived matricryptin (p1159) was shown to reduce left ventricular (LV) dilation and fibrosis after 7 days delivery in a mouse model of myocardial infarction (MI). This suggested p1159 long-term treatment post-MI could have beneficial effects and reduce/prevent adverse LV remodeling. This study aimed to test the potential of p1159 to reduce adverse cardiac remodeling in a chronic MI model and to elucidate p1159 mode-of-action. MATERIALS AND METHODS: Using a permanent occlusion MI rodent model, animals received p1159 or vehicle solution up to 28 days. We assessed peptide treatment effects on scar composition and structure and on systolic function. To assess peptide effects on scar vascularization, a cohort of mice were injected with Griffonia simplicifolia isolectin-B4. To investigate p1159 mode-of-action, LV fibroblasts from naïve animals were treated with increasing doses of p1159. KEY FINDINGS: Matricryptin p1159 significantly improved systolic function post-MI (2-fold greater EF compared to controls) by reducing left ventricular dilation and inducing the formation of a compliant and organized infarct scar, which promoted LV contractility and preserved the structural integrity of the heart. Specifically, infarcted scars from p1159-treated animals displayed collagen fibers aligned parallel to the epicardium, to resist circumferential stretching, with reduced levels of cross-linking, and improved tissue perfusion. In addition, we found that p1159 increases cardiac fibroblast migration by activating RhoA pathways via the membrane receptor integrin α4. SIGNIFICANCE: Our data indicate p1159 treatment reduced adverse LV remodeling post-MI by modulating the deposition, arrangement, and perfusion of the fibrotic scar.
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Cicatriz , Infarto del Miocardio , Ratones , Animales , Cicatriz/tratamiento farmacológico , Cicatriz/metabolismo , Colágeno/metabolismo , Infarto del Miocardio/metabolismo , Miocardio/metabolismo , Remodelación Ventricular , Fibrosis , Péptidos/metabolismo , Función Ventricular IzquierdaRESUMEN
Many studies have shown that mechanical forces can alter collagen degradation by proteases, and this mechanochemical effect may potentially serve an important role in determining extracellular matrix content and organization in load-bearing tissues. However, it is not yet known whether mechano-sensitive degradation depends on particular protease isoforms, nor is it yet known whether particular degradation byproducts can be altered by mechanical loading. In this study, we tested the hypothesis that different types of proteases exhibit different sensitivities to mechanical loading both in degradation rates and byproducts. Decellularized porcine pericardium samples were treated with human recombinant matrix metalloproteinases-1, -8, -9, cathepsin K, or a protease-free control while subjected to different levels of strain in a planar, biaxial mechanical tester. Tissue degradation was monitored by tracking the decay in mechanical stresses during displacement control tests, and byproducts were assessed by mass spectrometry analysis of the sample supernatant after degradation. Our key finding shows that cathepsin K-mediated degradation of collagenous tissue was enhanced with increasing strain, while MMP1-, MMP8-, and MMP9-mediated degradation were first decreased and then increased by strain. Degradation induced changes in tissue mechanical properties, and proteomic analysis revealed strain-sensitive degradome signatures with different ECM byproducts released at low vs. high strains. This evidence suggests a potentially new type of mechanobiology wherein mechanical forces alter the degradation products that can provide important signaling feedback functions during tissue remodeling.
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Matriz Extracelular , Proteómica , Porcinos , Animales , Humanos , Catepsina K/análisis , Endopeptidasas , Transducción de SeñalRESUMEN
Natural biomaterials hold enormous potential for tissue regeneration. The rapid advance of several tissue-engineered biomaterials, such as natural and synthetic polymer-based scaffolds, has led to widespread application of these materials in the clinic and in research. However, biomaterials can have limited repair capacity; obstacles result from immunogenicity, difficulties in mimicking native microenvironments, and maintaining the mechanical and biochemical (i.e., biomechanical) properties of native organs/tissues. The emergence of decellularized extracellular matrix (ECM)-derived biomaterials provides an attractive solution to overcome these hurdles since decellularized ECM provides a nonimmune environment with native three-dimensional structures and bioactive components. More importantly, decellularized ECM can be generated from the tissue of interest, such as the heart, and keep its native macro- and microstructure and tissue-specific composition. These decellularized cardiac matrices/scaffolds can then be reseeded using cardiac cells, and the resulting recellularized construct is considered an ideal choice for regenerating functional organs/tissues. Nonetheless, the decellularization process must be optimized and depends on tissue type, age, and functional goal. Although most decellularization protocols significantly reduce immunogenicity and deliver a matrix that maintains the tissue macrostructure, suboptimal decellularization can change ECM composition and microstructure, which affects the biomechanical properties of the tissue and consequently changes cell-matrix interactions and organ function. Herein, we review methods of decellularization, with particular emphasis on cardiac tissue, and how they can affect the biomechanics of the tissue, which in turn determines success of reseeding and in vivo viability. Moreover, we review recent developments in decellularized ECM-derived cardiac biomaterials and discuss future perspectives.
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Matriz Extracelular , Andamios del Tejido , Materiales Biocompatibles , Fenómenos Biomecánicos , Matriz Extracelular/química , Ingeniería de Tejidos/métodos , Andamios del Tejido/químicaRESUMEN
The great plasticity of cardiac fibroblasts allows them to respond quickly to myocardial injury and to contribute to the subsequent cardiac remodeling. Being the most abundant cell type (in numbers) in the heart, and a key participant in the several phases of tissue healing, the cardiac fibroblast is an excellent target for treating cardiac diseases. The development of cardiac fibroblast-specific approaches have, however, been difficult due to the lack of cellular specific markers. The development of genetic lineage tracing tools and Cre-recombinant transgenics has led to a huge acceleration in cardiac fibroblast research. Additionally, the use of novel targeted delivery approaches like nanoparticles and modified adenoviruses, has allowed researchers to define the developmental origin of cardiac fibroblasts, elucidate their differentiation pathways, and functional mechanisms in cardiac injury and disease. In this review, we will first characterize the roles of fibroblasts in the different stages of cardiac repair and then examine novel techniques targeting fibroblasts post-ischemic heart injury.
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Lesiones Cardíacas , Miocardio , Diferenciación Celular , Fibroblastos/metabolismo , Corazón , Lesiones Cardíacas/metabolismo , Humanos , Isquemia/metabolismo , Miocardio/metabolismoRESUMEN
Despite significant improvements in reperfusion strategies, acute coronary syndromes all too often culminate in a myocardial infarction (MI). The consequent MI can, in turn, lead to remodeling of the left ventricle (LV), the development of LV dysfunction, and ultimately progression to heart failure (HF). Accordingly, an improved understanding of the underlying mechanisms of MI remodeling and progression to HF is necessary. One common approach to examine MI pathology is with murine models that recapitulate components of the clinical context of acute coronary syndrome and subsequent MI. We evaluated the different approaches used to produce MI in mouse models and identified opportunities to consolidate methods, recognizing that reperfused and nonreperfused MI yield different responses. The overall goal in compiling this consensus statement is to unify best practices regarding mouse MI models to improve interpretation and allow comparative examination across studies and laboratories. These guidelines will help to establish rigor and reproducibility and provide increased potential for clinical translation.
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Investigación Biomédica/normas , Insuficiencia Cardíaca , Infarto del Miocardio , Daño por Reperfusión Miocárdica , Animales , Consenso , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/terapia , Masculino , Ratones , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Infarto del Miocardio/terapia , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/fisiopatología , Daño por Reperfusión Miocárdica/terapia , Reperfusión , Factores Sexuales , Especificidad de la EspecieRESUMEN
Evidence suggests the existence of an intracardiac dopaminergic system that plays a pivotal role in regulating cardiac function and fibrosis through G-protein coupled receptors, particularly mediated by dopamine receptor 3 (D3R). However, the expression of dopamine receptors in cardiac tissue and their role in cardiac fibroblast function is unclear. In this brief report, first we determined expression of D1R and D3R both in left ventricle (LV) tissue and fibroblasts. Then, we explored the role of D3R in the proliferation and migration of fibroblast cell cultures using both genetic and pharmaceutical approaches; specifically, we compared cardiac fibroblasts isolated from LV of wild type (WT) and D3R knockout (D3KO) mice in response to D3R-specific pharmacological agents. Finally, we determined if loss of D3R function could significantly alter LV fibroblast expression of collagen types I (Col1a1) and III (Col3a1). Cardiac fibroblast proliferation was attenuated in D3KO cells, mimicking the behavior of WT cardiac fibroblasts treated with D3R antagonist. In response to scratch injury, WT cardiac fibroblasts treated with the D3R agonist, pramipexole, displayed enhanced migration compared to control WT and D3KO cells. Loss of function in D3R resulted in attenuation of both proliferation and migration in response to scratch injury, and significantly increased the expression of Col3a1 in LV fibroblasts. These findings suggest that D3R may mediate cardiac fibroblast function during the wound healing response. To our knowledge this is the first report of D3R's expression and functional significance directly in mouse cardiac fibroblasts.
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There is a lack of understanding in the cardiac remodeling field regarding the use of nonreperfused myocardial infarction (MI) and reperfused MI in animal models of MI. This Perspectives summarizes the consensus of the authors regarding how to select the optimum model for your experiments and is a part of ongoing efforts to establish rigor and reproducibility in cardiac physiology research.
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Infarto del Miocardio , Isquemia Miocárdica , Reperfusión Miocárdica , Animales , Modelos Animales de Enfermedad , CorazónRESUMEN
INTRODUCTION: Amlodipine overdoses have significant cardiac toxicity and are difficult to treat. Methylene blue has potential as a treatment for overdoses. METHODS: A randomized controlled study of methylene blue as a treatment for amlodipine toxicity was conducted in C57Bl/6 mice. A baseline echocardiography was followed by gavage administration of amlodipine (90â¯mg/kg). Five minutes after gavage, animals received either vehicle solution (controls) or methylene blue (20â¯mg/kg) by intra-peritoneal injection. Animals were continuously monitored, and cardiac parameters were acquired every 15â¯min up to two hours. RESULTS: Only 50% of control animals survived to the two-hour endpoint compared to 83% that received methylene blue. Amlodipine delivery induced significant reduction in left ventricular ejection fraction (EF), fractional shortening (FS), stroke volume (SV), and cardiac output (CO) in the vehicle treated animals relative to animals in the treatment group (pâ¯<â¯0.05 vehicle versus Methylene blue for EF, FS, SV, CO, and HR). DISCUSSION: The amlodipine dose induced cardiotoxicity that were effects were more pronounced in the untreated group. 50% vehicle controls quickly progressed into heart failure (within 90â¯min of exposure) and did not survive the two h observation endpoint. Distinctly, only one animal from the Methylene blue treatment group did not survive (83% survival) the study. Additionally, the surviving animals from the Methylene blue group displayed significantly higher ejection fraction, fractional shortening, stroke volume, and cardiac output compared to vehicle group, indicating that methylene blue preserved cardiac function. CONCLUSION: In this mouse model of amlodipine overdose, methylene blue decreased cardiac toxicity.
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Amlodipino , Cardiotoxicidad , Sobredosis de Droga , Azul de Metileno , Animales , Ratones , Amlodipino/envenenamiento , Modelos Animales de Enfermedad , Sobredosis de Droga/tratamiento farmacológico , Azul de Metileno/farmacología , Ratones Endogámicos C57BL , Volumen Sistólico/efectos de los fármacos , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
Morphine is routinely used for pain management in heart failure patients. However, extended morphine exposure associates with major adverse cardiovascular events. Reports link the dopamine receptor D2-family with morphine-induced nociception modulation. This study first assessed whether morphine induces cardiac remodeling in healthy mice, then whether DRD3 agonist (DRD3ag, D2-family member) adjunct therapy prevents morphine-induced cardiac remodeling. Mice received morphine (2 mg/kg/day i. p.) for 7 days (D7) and were either euthanized at D7 or kept 7 more days without morphine (i.e. withdrawal period, D8-D14): G1, morphine; G2, morphine/DRD3ag; G3, morphine + withdrawal; G4, morphine/DRD3ag + withdrawal; G5, morphine + withdrawal/DRD3ag. A separate cohort of animals were used as naïve tissues. We evaluated functional and molecular parameters of cardiac remodeling. Although we did not observe significant differences in systolic function, morphine induced both interstitial fibrosis and cardiomyocyte hypertrophy. Interestingly, DRD3ag abolished these effects. Compared to naïve tissues, collagen 1 increased after withdrawal in G3 and G4 and collagen 3 increased in G1-G4 but at higher levels in G1 and G2. Only G5 did not show collagen differences compared to naïve, suggesting DRD3ag treatment during withdrawal may be beneficial and prevent morphine-induced fibrosis. Smad2/3 phosphorylation increased during withdrawal, indicating a likely upstream pathway for the observed morphine-induced fibrosis. Overall, our data suggest that DRD3ag adjunct therapy decreases morphine-induced adverse cardiac remodeling.
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Morfina/efectos adversos , Miocardio/patología , Pramipexol/farmacología , Receptores de Dopamina D3/agonistas , Animales , Colágeno/metabolismo , Fibrosis , Hipertrofia , Masculino , Ratones Endogámicos C57BL , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Sístole/efectos de los fármacosRESUMEN
Alterations in the composition of the extracellular matrix (ECM) critically regulate the cellular responses in tissue repair, remodeling, and fibrosis. After injury, proteolytic degradation of ECM generates bioactive ECM fragments, named matricryptins, exposing cryptic sites with actions distinct from the parent molecule. Matricryptins contribute to the regulation of inflammatory, reparative, and fibrogenic cascades through effects on several different cell types both in acute and chronic settings. Fibroblasts play a major role in matricryptin generation not only as the main cellular source of ECM proteins, but also as producers of matrix-degrading proteases. Moreover, several matricryptins exert fibrogenic or reparative actions by modulating fibroblast phenotype and function. This review manuscript focuses on the mechanisms of matricyptin generation in injured and remodeling tissues with an emphasis on fibroblast-matricryptin interactions.
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Colágeno/genética , Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Fibrosis/genética , Péptidos/genética , Animales , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Colágeno/clasificación , Colágeno/metabolismo , Elastina/genética , Elastina/metabolismo , Células Endoteliales/metabolismo , Células Endoteliales/patología , Matriz Extracelular/química , Matriz Extracelular/patología , Fibroblastos/química , Fibroblastos/patología , Fibronectinas/genética , Fibronectinas/metabolismo , Fibrosis/metabolismo , Fibrosis/patología , Regulación de la Expresión Génica , Proteoglicanos de Heparán Sulfato/genética , Proteoglicanos de Heparán Sulfato/metabolismo , Humanos , Neutrófilos/metabolismo , Neutrófilos/patología , Péptidos/metabolismo , Transducción de Señal , Tenascina/genética , Tenascina/metabolismo , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Cicatrización de Heridas/genéticaRESUMEN
Age-related remodeling of the heart causes structural and functional changes in the left ventricle (LV) that are associated with a high index of morbidities and mortality worldwide. Some cardiac pathologies in the elderly population vary between genders revealing that cardiac remodeling during aging may be sex-dependent. Herein, we analyzed the effects of cardiac aging in male and female C57Bl/6 mice in four age groups, 3, 6, 12, and 18 month old (n = 6-12 animals/sex/age), to elucidate which age-related characteristics of LV remodeling are sex-specific. We focused particularly in parameters associated with age-dependent remodeling of the LV extracellular matrix (ECM) that are involved in collagen metabolism. LV function and anatomical structure were assessed both by conventional echocardiography and speckle tracking echocardiography (STE). We then measured ECM proteins that directly affect LV contractility and remodeling. All data were analyzed across ages and between sexes and were directly linked to LV functional changes. Echocardiography confirmed an age-dependent decrease in chamber volumes and LV internal diameters, indicative of concentric remodeling. As in humans, animals displayed preserved ejection fraction with age. Notably, changes to chamber dimensions and volumes were temporally distinct between sexes. Complementary to the traditional echocardiography, STE revealed that circumferential strain rate declined in 18 month old females, compared to younger animals, but not in males, suggesting STE as an earlier indicator for changes in cardiac function between sexes. Age-dependent collagen deposition and expression in the endocardium did not differ between sexes; however, other factors involved in collagen metabolism were sex-specific. Specifically, while decorin, osteopontin, Cthrc1, and Ddr1 expression were age-dependent but sex-independent, periostin, lysyl oxidase, and Mrc2 displayed age-dependent and sex-specific differences. Moreover, our data also suggest that with age males and females have distinct TGFß signaling pathways. Overall, our results give evidence of sex-specific molecular changes during physiological cardiac remodeling that associate with age-dependent structural and functional dysfunction. These data highlight the importance of including sex-differences analysis when studying cardiac aging.
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Matriz Extracelular/metabolismo , Corazón/fisiopatología , Caracteres Sexuales , Animales , Peso Corporal , Cardiomegalia/metabolismo , Cardiomegalia/patología , Cardiomegalia/fisiopatología , Colágeno/metabolismo , Electrocardiografía , Femenino , Corazón/diagnóstico por imagen , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/fisiopatología , Homeostasis , Modelos Lineales , Masculino , Ratones Endogámicos C57BL , Contracción Miocárdica , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Proteoglicanos/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Remodelación VentricularRESUMEN
Exercise capacity is a strong predictor of all-cause mortality. Skeletal muscle mitochondrial respiratory capacity, its biggest contributor, adapts robustly to changes in energy demands induced by contractile activity. While transcriptional regulation of mitochondrial enzymes has been extensively studied, there is limited information on how mitochondrial membrane lipids are regulated. Here, we show that exercise training or muscle disuse alters mitochondrial membrane phospholipids including phosphatidylethanolamine (PE). Addition of PE promoted, whereas removal of PE diminished, mitochondrial respiratory capacity. Unexpectedly, skeletal muscle-specific inhibition of mitochondria-autonomous synthesis of PE caused respiratory failure because of metabolic insults in the diaphragm muscle. While mitochondrial PE deficiency coincided with increased oxidative stress, neutralization of the latter did not rescue lethality. These findings highlight the previously underappreciated role of mitochondrial membrane phospholipids in dynamically controlling skeletal muscle energetics and function.
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Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo , Músculo Esquelético/fisiología , Consumo de Oxígeno , Fosfatidiletanolaminas/metabolismo , Condicionamiento Físico Animal , Animales , Carboxiliasas/fisiología , Tolerancia al Ejercicio , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias/patología , Membranas Mitocondriales/metabolismo , Proteínas Mitocondriales/genética , Contracción Muscular , Mioblastos/citología , Mioblastos/metabolismo , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Barth Syndrome (BTHS) is an X-linked recessive disorder characterized by cardiomyopathy and muscle weakness. The underlying cause of BTHS is a mutation in the tafazzin (TAZ) gene, a key enzyme of cardiolipin biosynthesis. The lack of CL arising from loss of TAZ function results in destabilization of the electron transport system, promoting oxidative stress that is thought to contribute to development of cardioskeletal myopathy. Indeed, in vitro studies demonstrate that mitochondria-targeted antioxidants improve contractile capacity in TAZ-deficient cardiomyocytes. The purpose of the present study was to determine if resolving mitochondrial oxidative stress would be sufficient to prevent cardiomyopathy and skeletal myopathy in vivo using a mouse model of BTHS. To this end we crossed mice that overexpress catalase in the mitochondria (MCAT mice) with TAZ-deficient mice (TAZKD) to produce TAZKD mice that selectively overexpress catalase in the mitochondria (TAZKD+MCAT mice). TAZKD+MCAT mice exhibited decreased mitochondrial H2O2 emission and lipid peroxidation compared to TAZKD littermates, indicating decreased oxidative stress. Despite the improvements in oxidative stress, TAZKD+MCAT mice developed cardiomyopathy and mild muscle weakness similar to TAZKD littermates. These findings indicate that resolving oxidative stress is not sufficient to suppress cardioskeletal myopathy associated with BTHS.
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Síndrome de Barth/genética , Cardiomiopatías/genética , Catalasa/genética , Estrés Oxidativo/genética , Factores de Transcripción/genética , Aciltransferasas , Animales , Antioxidantes/administración & dosificación , Síndrome de Barth/tratamiento farmacológico , Síndrome de Barth/fisiopatología , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/patología , Catalasa/antagonistas & inhibidores , Modelos Animales de Enfermedad , Humanos , Peróxido de Hidrógeno/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Peroxidación de Lípido/genética , Mitocondrias/enzimología , Mutación , Contracción Miocárdica/genética , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Estrés Oxidativo/efectos de los fármacosRESUMEN
The generation of big data has enabled systems-level dissections into the mechanisms of cardiovascular pathology. Integration of genetic, proteomic, and pathophysiological variables across platforms and laboratories fosters discoveries through multidisciplinary investigations and minimizes unnecessary redundancy in research efforts. The Mouse Heart Attack Research Tool (mHART) consolidates a large data set of over 10 yr of experiments from a single laboratory for cardiovascular investigators to generate novel hypotheses and identify new predictive markers of progressive left ventricular remodeling after myocardial infarction (MI) in mice. We designed the mHART REDCap database using our own data to integrate cardiovascular community participation. We generated physiological, biochemical, cellular, and proteomic outputs from plasma and left ventricles obtained from post-MI and no-MI (naïve) control groups. We included both male and female mice ranging in age from 3 to 36 mo old. After variable collection, data underwent quality assessment for data curation (e.g., eliminate technical errors, check for completeness, remove duplicates, and define terms). Currently, mHART 1.0 contains >888,000 data points and includes results from >2,100 unique mice. Database performance was tested, and an example is provided to illustrate database utility. This report explains how the first version of the mHART database was established and provides researchers with a standard framework to aid in the integration of their data into our database or in the development of a similar database. NEW & NOTEWORTHY The Mouse Heart Attack Research Tool combines >888,000 cardiovascular data points from >2,100 mice. We provide this large data set as a REDCap database to generate novel hypotheses and identify new predictive markers of adverse left ventricular remodeling following myocardial infarction in mice and provide examples of use. The Mouse Heart Attack Research Tool is the first database of this size that integrates data sets across platforms that include genomic, proteomic, histological, and physiological data.