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1.
J Cardiovasc Transl Res ; 13(3): 431-450, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32642841

RESUMO

In the field of cardio-oncology, it is well recognised that despite the benefits of chemotherapy in treating and possibly curing cancer, it can cause catastrophic damage to bystander tissues resulting in a range of potentially of life-threatening cardiovascular toxicities, and leading to a number of damaging side effects including heart failure and myocardial infarction. Cardiotoxicity is responsible for significant morbidity and mortality in the long-term in oncology patients, specifically due to left ventricular dysfunction. There is increasing emphasis on the early use of biomarkers in order to detect the cardiotoxicity at a stage before it becomes irreversible. The most important markers of cardiac injury are cardiac troponin and natriuretic peptides, whilst markers of inflammation such as interleukin-6, C-reactive protein, myeloperoxidase, Galectin-3, growth differentiation factor-15 are under investigation for their use in detecting cardiotoxicity early. In addition, microRNAs, genome-wide association studies and proteomics are being studied as novel markers of cardiovascular injury or inflammation. The aim of this literature review is to discuss the evidence base behind the use of these biomarkers for the detection of cardiotoxicity.


Assuntos
Antineoplásicos/efeitos adversos , Biomarcadores/metabolismo , Sobreviventes de Câncer , Cardiologia , Cardiopatias/induzido quimicamente , Oncologia , Miócitos Cardíacos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Biomarcadores/sangue , Cardiotoxicidade , Cardiopatias/diagnóstico , Cardiopatias/metabolismo , Cardiopatias/terapia , Humanos , Miócitos Cardíacos/metabolismo , Valor Preditivo dos Testes , Prognóstico , Medição de Risco , Fatores de Risco
2.
PLoS One ; 15(7): e0232507, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32645007

RESUMO

Sex-related differences in cardiovascular diseases are highly complex in humans and model-dependent in experimental laboratory animals. The objective of this work was to comprehensively investigate key sex differences in the response to acute and prolonged adrenergic stimulation in C57Bl/6NCrl mice. Cardiac function was assessed by trans-thoracic echocardiography before and after acute adrenergic stimulation (a single sub-cutaneous dose of isoproterenol 10 mg/kg) in 15 weeks old male and female C57Bl/6NCrl mice. Thereafter, prolonged adrenergic stimulation was achieved by sub-cutaneous injections of isoproterenol 10 mg/kg/day for 14 days in male and female mice. Cardiac function and morphometry were assessed by trans-thoracic echocardiography on the 15th day. Thereafter, the mice were euthanized, and the hearts were collected. Histopathological analysis of myocardial tissue was performed after staining with hematoxylin & eosin, Masson's trichrome and MAC-2 antibody. Gene expression of remodeling and fibrotic markers was assessed by real-time PCR. Cardiac function and morphometry were also measured before and after isoproterenol 10 mg/kg/day for 14 days in groups of gonadectomized male and female mice and sham-operated controls. In the current work, there were no statistically significant differences in the positive inotropic and chronotropic effects of isoproterenol between male and female C57Bl/6NCrl. After prolonged adrenergic stimulation, there was similar degree of cardiac dysfunction, cardiac hypertrophy, and myocardial fibrosis in male and female mice. Similarly, prolonged isoproterenol administration induced hypertrophic and fibrotic genes in hearts of male and female mice to the same extent. Intriguingly, gonadectomy of male and female mice did not have a significant impact on isoproterenol-induced cardiac dysfunction as compared to sham-operated animals. The current work demonstrated lack of significant sex-related differences in isoproterenol-induced cardiac hypertrophy, dysfunction, and fibrosis in C57Bl/6NCrl mice. This study suggests that female sex may not be sufficient to protect the heart in this model of isoproterenol-induced cardiac dysfunction and underscores the notion that sexual dimorphism in cardiovascular diseases is highly model-dependent.


Assuntos
Cardiopatias/fisiopatologia , Caracteres Sexuais , Animais , Biomarcadores/metabolismo , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Ecocardiografia , Feminino , Cardiopatias/induzido quimicamente , Cardiopatias/metabolismo , Cardiopatias/patologia , Isoproterenol/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ovariectomia
3.
Croat Med J ; 61(2): 126-138, 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32378379

RESUMO

Mitochondria are involved in crucial homeostatic processes in the cell: the production of adenosine triphosphate and reactive oxygen species, and the release of pro-apoptotic molecules. Thus, cell survival depends on the maintenance of proper mitochondrial function by mitochondrial quality control. The most important mitochondrial quality control mechanisms are mitochondrial unfolded protein response, mitophagy, biogenesis, and fusion-fission dynamics. This review deals with mitochondrial quality control in heart diseases, especially myocardial infarction and heart failure. Some previous studies have demonstrated that the activation of mitochondrial quality control mechanisms may be beneficial for the heart, while others have shown that it may lead to heart damage. Our aim was to describe the mechanisms by which mitochondrial quality control contributes to heart protection or damage and to provide evidence that may resolve the seemingly contradictory results from the previous studies.


Assuntos
Cardiopatias/metabolismo , Mitocôndrias/metabolismo , Mitofagia/fisiologia , Resposta a Proteínas não Dobradas/fisiologia , Envelhecimento/fisiologia , Humanos
4.
Int J Cardiovasc Imaging ; 36(9): 1761-1769, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32409978

RESUMO

Right ventricular biopsy represents the gold standard for the assessment of myocardial fibrosis and collagen content. This invasive technique, however, is accompanied by perioperative complications and poor reproducibility. Extracellular volume (ECV) measured through cardiovascular magnetic resonance (CMR) has emerged as a valid surrogate method to assess fibrosis non-invasively. Nonetheless, ECV provides an overestimation of collagen concentration since it also considers interstitial space. Our study aims to investigate the feasibility of estimating total collagen volume (TCV) through CMR by comparing it with the TCV measured at histology. Seven healthy Landrace pigs were acutely instrumented closed-chest and transported to the MRI facility for measurements. For each protocol, CMR imaging at 3T was acquired. MEDIS software was used to analyze T1 mapping and ECV for both the left ventricular myocardium (LVmyo) and left ventricular septum (LVseptum). ECV was then used to estimate TCVCMR at LVmyo and LVseptum following previously published formulas. Tissues were prepared following an established protocol and stained with picrosirius red to analyze the TCVhisto in LVmyo and LVseptum. TCV measured at LVmyo and LVseptum with both histology (8 ± 5 ml and 7 ± 3 ml, respectively) and T1-Mapping (9 ± 5 ml and 8 ± 6 ml, respectively) did not show any regional differences. TCVhisto and TCVCMR showed a good level of data agreement by Bland-Altman analysis. Estimation of TCV through CMR may be a promising way to non-invasively assess myocardial collagen content and may be useful to track disease progression or treatment response.


Assuntos
Colágeno/análise , Cardiopatias/diagnóstico por imagem , Coração/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética , Miocárdio/química , Animais , Biópsia , Estudos de Viabilidade , Fibrose , Cardiopatias/metabolismo , Cardiopatias/patologia , Miocárdio/patologia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Sus scrofa
5.
Am J Physiol Cell Physiol ; 319(1): C166-C182, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32432929

RESUMO

This review aims to highlight the normal physiological remodeling that occurs in healthy aging hearts, including changes that occur in contractility, conduction, valve function, large and small coronary vessels, and the extracellular matrix. These "normal" age-related changes serve as the foundation that supports decreased plasticity and limited ability for tissue remodeling during pathophysiological states such as myocardial ischemia and heart failure. This review will identify populations at greater risk for poor tissue remodeling in advanced age along with present and future therapeutic strategies that may ameliorate dysfunctional tissue remodeling in aging hearts.


Assuntos
Envelhecimento Saudável/patologia , Cardiopatias/patologia , Miocárdio/patologia , Remodelação Ventricular/fisiologia , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Envelhecimento Saudável/metabolismo , Cardiopatias/metabolismo , Humanos , Miocárdio/metabolismo
7.
PLoS One ; 15(4): e0231905, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32315372

RESUMO

Myocardial fibrosis is often associated with cardiac hypertrophy; indeed, fibrosis is one of the most critical factors affecting prognosis. We aimed to identify the molecules involved in promoting fibrosis under hypertrophic stimuli. We previously established a rat model of cardiac hypertrophy by pulmonary artery banding, in which approximately half of the animals developed fibrosis in the right ventricle. Here, we first comprehensively analyzed mRNA expression in the right ventricle with or without fibrosis in pulmonary artery banding model rats by DNA microarray analysis (GSE141650 at NCBI GEO). The expression levels of 19 genes were up-regulated more than 1.5-fold in fibrotic hearts compared with non-fibrotic hearts. Among them, fibrosis growth factor (FGF) 23 showed one of the biggest increases in expression. Real-time PCR analysis also revealed that, among the FGF receptor (FGFR) family, FGFR1 was highly expressed in fibrotic hearts. We then found that FGF23 was expressed predominantly in cardiomyocytes, while FGFR1 was predominantly expressed in fibroblasts in the rat ventricle. Next, we added FGF23 and transforming growth factor (TGF)-ß1 (10-50 ng/mL of each) to isolated fibroblasts from normal adult rat ventricles and cultured them for three days. While FGF23 itself did not directly affect the expression levels of any fibrosis-related mRNAs, FGF23 enhanced the effect of TGF-ß1 on increasing the expression levels of α-smooth muscle actin (α-SMA) mRNA. This increase in xx-SMA mRNA levels due to the combination of TGF-ß1 and FGF23 was attenuated by the inhibition of FGFR1 or the knockdown of FGFR1 in fibroblasts. Thus, FGF23 synergistically promoted the activation of fibroblasts with TGF-ß1, transforming fibroblasts into myofibroblasts via FGFR1. Thus, we identified FGF23 as a paracrine factor secreted from cardiomyocytes to promote cardiac fibrosis under conditions in which TGF-ß1 is activated. FGF23 could be a possible target to prevent fibrosis following myocardial hypertrophy.


Assuntos
Fatores de Crescimento de Fibroblastos/farmacologia , Cardiopatias/patologia , Fator de Crescimento Transformador beta1/farmacologia , Regulação para Cima/efeitos dos fármacos , Actinas/genética , Actinas/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Fibrose , Cardiopatias/metabolismo , Masculino , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo
9.
Adv Exp Med Biol ; 1221: 721-745, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32274734

RESUMO

Traditionally, the management of diabetes has focused mainly on controlling high blood glucose levels. Unfortunately, despite valiant efforts to normalize this blood glucose, poor medication management predisposes these patients to heart failure. Following diabetes, how the heart utilizes different sources of fuel for energy is key to the development of heart failure. The diabetic heart switches from using both glucose and fats, to predominately using fats as an energy resource for maintaining its activities. This transformation to using fats as an exclusive source of energy is helpful in the initial stages of the disease and is tightly controlled. However, over the progression of diabetes, there is a loss of this controlled supply and use of fats, which ultimately has terrible consequences since the uncontrolled use of fats produces toxic by-products which weaken heart function and cause heart disease. Heparanase is a key player that directs how much fats are provided to the heart and does so in association with several partners like LPL and VEGFs. Together, they regulate the amount of fats supplied, and their subsequent breakdown to provide energy. Following diabetes, there is a disruption in this network resulting in fat oversupply and cell death. Understanding how the heparanase-LPL-VEGFs "ensemble" cooperates, and its dysfunction in the diabetic heart would be useful in restoring metabolic equilibrium and limiting diabetes-related cardiac damage.


Assuntos
Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Células Endoteliais/enzimologia , Glucuronidase/metabolismo , Cardiopatias/metabolismo , Cardiopatias/patologia , Miócitos Cardíacos/enzimologia , Diabetes Mellitus/enzimologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Cardiopatias/enzimologia , Humanos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia
10.
J Cardiovasc Transl Res ; 13(3): 402-416, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32253744

RESUMO

Cancer therapies have been evolving from conventional chemotherapeutics to targeted agents. This has fulfilled the hope of greater efficacy but unfortunately not of greater safety. In fact, a broad spectrum of toxicities can be seen with targeted therapies, including cardiovascular toxicities. Among these, cardiomyopathy and heart failure have received greatest attention, given their profound implications for continuation of cancer therapies and cardiovascular morbidity and mortality. Prediction of risk has always posed a challenge and even more so with the newer targeted agents. The merits of accurate risk prediction, however, are very evident, e.g. facilitating treatment decisions even before the first dose is given. This is important for agents with a long half-life and high potential to induced life-threatening cardiac complications, such as myocarditis with immune checkpoint inhibitors. An opportunity to address these needs in the field of cardio-oncology is provided by the expanding repertoire of "-omics" and other tools in precision medicine and their integration in a systems biology approach. This may allow for new insights into patho-mechanisms and the creation of more precise and cost-effective risk prediction tools with the ultimate goals of improved therapy decisions and prevention of cardiovascular complications. Herein, we explore this topic as a future approach to translating the complexity of cardio-oncology to the reality of patient care.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Sobreviventes de Câncer , Cardiologia , Cardiopatias/induzido quimicamente , Oncologia , Neoplasias/tratamento farmacológico , Medicina de Precisão , Inibidores de Proteínas Quinases/efeitos adversos , Biologia de Sistemas , Animais , Cardiotoxicidade , Cardiopatias/genética , Cardiopatias/metabolismo , Humanos , Terapia de Alvo Molecular , Neoplasias/enzimologia , Neoplasias/imunologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Medição de Risco , Fatores de Risco
11.
Am J Physiol Heart Circ Physiol ; 318(5): H1162-H1175, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32216616

RESUMO

Nitric oxide (NO) and S-nitrosothiol (SNO) are considered cardio- and vasoprotective substances. We now understand that one mechanism in which NO/SNOs provide cardiovascular protection is through their direct inhibition of cardiac G protein-coupled receptor (GPCR) kinase 2 (GRK2) activity via S-nitrosylation of GRK2 at cysteine 340 (C340). This maintains GPCR homeostasis, including ß-adrenergic receptors, through curbing receptor GRK2-mediated desensitization. Previously, we have developed a knockin mouse (GRK2-C340S) where endogenous GRK2 is resistant to dynamic S-nitrosylation, which led to increased GRK2 desensitizing activity. This unchecked regulation of cardiac GRK2 activity resulted in significantly more myocardial damage after ischemic injury that was resistant to NO-mediated cardioprotection. Although young adult GRK2-C340S mice show no overt phenotype, we now report that as these mice age, they develop significant cardiovascular dysfunction due to the loss of SNO-mediated GRK2 regulation. This pathological phenotype is apparent as early as 12 mo of age and includes reduced cardiac function, increased cardiac perivascular fibrosis, and maladaptive cardiac hypertrophy, which are common maladies found in patients with cardiovascular disease (CVD). There are also vascular reactivity and aortic abnormalities present in these mice. Therefore, our data demonstrate that a chronic and global increase in GRK2 activity is sufficient to cause cardiovascular remodeling and dysfunction, likely due to GRK2's desensitizing effects in several tissues. Because GRK2 levels have been reported to be elevated in elderly CVD patients, GRK2-C340 mice can give insight into the aged-molecular landscape leading to CVD.NEW & NOTEWORTHY Research on G protein-coupled receptor kinase 2 (GRK2) in the setting of cardiovascular aging is largely unknown despite its strong established functions in cardiovascular physiology and pathophysiology. This study uses a mouse model of chronic GRK2 overactivity to further investigate the consequences of long-term GRK2 on cardiac function and structure. We report for the first time that chronic GRK2 overactivity was able to cause cardiac dysfunction and remodeling independent of surgical intervention, highlighting the importance of GRK activity in aged-related heart disease.


Assuntos
Envelhecimento/fisiologia , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Cardiopatias/etiologia , Coração/fisiologia , Miocárdio/metabolismo , Óxido Nítrico/metabolismo , Envelhecimento/metabolismo , Animais , Feminino , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Coração/crescimento & desenvolvimento , Coração/fisiopatologia , Cardiopatias/metabolismo , Homeostase , Masculino , Camundongos , Mutação
12.
Artigo em Inglês | MEDLINE | ID: mdl-32167781

RESUMO

The roles of ACE-independent ANG II production via chymase and therapeutic potential of epoxyeicosatrienoic acids (EETs) in fructose-induced metabolic syndrome (MetS) in the adolescent population remain elusive. Thus we tested the hypothesis that a high-fructose diet (HFD) in young rats elicits chymase-dependent increases in ANG II production and oxidative stress, responses that are reversible by 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), an inhibitor of soluble epoxide hydrolase (sEH) that metabolizes EETs. Three groups of weanling rats (21-day-old) were fed a normal diet, 60% HFD, and HFD with TPPU, respectively, for 30 days. HFD rats developed MetS, characterized by hyperglycemia, hyperinsulinemia, and hypertension and associated with decreases in cardiac output and stroke volume and loss of nitric oxide (NO) modulation of myocardial oxygen consumption; all impairments were normalized by TPPU that significantly elevated circulating 11,12-EET, a major cardiac EET isoform. In the presence of comparable cardiac angiotensin-converting enzyme (ACE) expression/activity among the three groups, HFD rats exhibited significantly greater chymase-dependent ANG II formation in hearts, as indicated by an augmented cardiac chymase content as a function of enhanced mast cell degranulation. The enhanced chymase-dependent ANG II production was paralleled with increases in ANG II type 1 receptor (AT1R) expression and NADPH oxidase (Nox)-induced superoxide, alterations that were significantly reversed by TPPU. Conversely, HFD-induced downregulation of cardiac ACE2, followed by a lower Ang-(1-7) level displayed in an TPPU-irreversible manner. In conclusion, HFD-driven adverse chymase/ANG II/Nox/superoxide signaling in young rats was prevented by inhibition of sEH via, at least in part, an EET-mediated stabilization of mast cells, highlighting chymase and sEH as therapeutic targets during treatment of MetS.NEW & NOTEWORTHY As the highest fructose consumers, the adolescent population is highly susceptible to the metabolic syndrome, where increases in mast cell chymase-dependent formation of ANG II, ensued by cardiometabolic dysfunction, are reversible in response to inhibition of soluble epoxide hydrolase (sEH). This study highlights chymase and sEH as therapeutic targets and unravels novel avenues for the development of optimal strategies for young patients with fructose-induced metabolic syndrome.


Assuntos
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Angiotensina II/metabolismo , Quimases/metabolismo , Frutose/efeitos adversos , Cardiopatias/metabolismo , Síndrome Metabólica/complicações , Ácido 8,11,14-Eicosatrienoico/metabolismo , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Débito Cardíaco , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Epóxido Hidrolases/antagonistas & inibidores , Coração/efeitos dos fármacos , Coração/fisiopatologia , Cardiopatias/tratamento farmacológico , Cardiopatias/etiologia , Frequência Cardíaca , Masculino , Síndrome Metabólica/etiologia , Miocárdio/metabolismo , Estresse Oxidativo , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley
13.
Mol Med Rep ; 21(3): 1097-1106, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32016456

RESUMO

The aim of the present study was to investigate the effect of urantide on collagen metabolism in the hearts of rats with atherosclerosis (AS) by evaluating the expression of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway constituents. Urantide was delivered to rats with AS via tail vein injection for 3, 7 and 14 days. Serological indicators were identified by an automated biochemical analyzer. Histomorphological changes in the cardiac tissue of rats were observed by pathological staining techniques. The expression of genes and proteins was assessed using reverse transcription­quantitative PCR and western blot analysis, respectively. Localization of proteins was detected by immunofluorescence. Overexpression of urotensin II (UII) and its receptor, G protein­coupled receptor 14 (GPR14), was observed in the hearts of rats with AS and the expression of both proteins significantly declined after urantide administration. Triglyceride, total cholesterol, low­density lipoprotein, high­density lipoprotein and calcium levels were improved in rats with AS following treatment with urantide. Notably, urantide was able to antagonize the UII/GPR14 system. Urantide treatment resulted in markedly decreased expression levels of matrix metalloproteinase 2 (MMP­2), collagen type I/III, and genes and proteins in the JAK2/STAT3 pathway. By contrast, TIMP metallopeptidase inhibitor 2 (TIMP­2) levels were increased. In addition, the MMP­2/TIMP­2 protein ratio was significantly decreased in rats treated with urantide compared with AS rats with no urantide treatment. Constituents of the JAK2/STAT3 pathway and collagen type I/III were found to be localized in the diseased tissue and blood vessels of the hearts of rats with AS. In conclusion, urantide was able to effectively block the UII/GPR14 system by regulating the JAK2/STAT3 pathway and collagen metabolism. Inhibition of the UII/GPR14 system may prevent and potentially treat atherosclerotic myocardial fibrosis. Based on the current results, it was hypothesized that collagen metabolism may be associated with the JAK2/STAT3 pathway.


Assuntos
Aterosclerose/metabolismo , Colágeno/metabolismo , Fibrose/metabolismo , Cardiopatias/metabolismo , Janus Quinase 2/metabolismo , Fragmentos de Peptídeos/farmacologia , Fator de Transcrição STAT3/metabolismo , Urotensinas/farmacologia , Animais , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Aterosclerose/tratamento farmacológico , Aterosclerose/patologia , Modelos Animais de Doenças , Fibrose/tratamento farmacológico , Fibrose/patologia , Cardiopatias/tratamento farmacológico , Cardiopatias/patologia , Janus Quinase 2/genética , Lipoproteínas LDL/metabolismo , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Ratos , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Fator de Transcrição STAT3/genética , Transdução de Sinais/efeitos dos fármacos , Urotensinas/genética , Urotensinas/metabolismo
14.
PLoS One ; 15(1): e0227449, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32004354

RESUMO

The SOD3 variant, SOD3R213G, results from substitution of arginine to glycine at amino acid 213 (R213G) in its heparin binding domain (HBD) and is a common genetic variant, reported to be associated with ischemic heart disease. However, little is understood about the role of SOD3R213G in innate immune function, and how it leads to dysfunction of the cardiovascular system. We observed pathologic changes in SOD3R213G transgenic (Tg) mice, including cystic medial degeneration of the aorta, heart inflammation, and increased circulating and organ infiltrating neutrophils. Interestingly, SOD3R213G altered the profile of SOD3 interacting proteins in neutrophils in response to G-CSF. Unexpectedly, we found that G-CSF mediated tyrosine phosphatase, SH-PTP1 was down-regulated in the neutrophils of SOD3R213G overexpressing mice. These effects were recovered by reconstitution with Wt SOD3 expressing bone marrow cells. Overall, our study reveals that SOD3R213G plays a crucial role in the function of the cardiovascular system by controlling innate immune response and signaling. These results suggest that reconstitution with SOD3 expressing bone marrow cells may be a therapeutic strategy to treat SOD3R213G mediated diseases.


Assuntos
Infiltração de Neutrófilos/fisiologia , Neutrófilos/metabolismo , Superóxido Dismutase/metabolismo , Animais , Aorta/metabolismo , Aorta/patologia , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Proliferação de Células , Modelos Animais de Doenças , Regulação para Baixo , Fator Estimulador de Colônias de Granulócitos/metabolismo , Cardiopatias/imunologia , Cardiopatias/metabolismo , Cardiopatias/patologia , Imunidade Inata , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutagênese Sítio-Dirigida , Miocárdio/metabolismo , Miocárdio/patologia , Neutrófilos/citologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Receptores CCR2/metabolismo , Transdução de Sinais , Superóxido Dismutase/genética
15.
Nat Commun ; 11(1): 965, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32075961

RESUMO

The sarco-endoplasmic reticulum (SR/ER) plays an important role in the development and progression of many heart diseases. However, many aspects of its structural organization remain largely unknown, particularly in cells with a highly differentiated SR/ER network. Here, we report a cardiac enriched, SR/ER membrane protein, REEP5 that is centrally involved in regulating SR/ER organization and cellular stress responses in cardiac myocytes. In vitro REEP5 depletion in mouse cardiac myocytes results in SR/ER membrane destabilization and luminal vacuolization along with decreased myocyte contractility and disrupted Ca2+ cycling. Further, in vivo CRISPR/Cas9-mediated REEP5 loss-of-function zebrafish mutants show sensitized cardiac dysfunction upon short-term verapamil treatment. Additionally, in vivo adeno-associated viral (AAV9)-induced REEP5 depletion in the mouse demonstrates cardiac dysfunction. These results demonstrate the critical role of REEP5 in SR/ER organization and function as well as normal heart function and development.


Assuntos
Coração/fisiopatologia , Proteínas de Membrana/deficiência , Retículo Sarcoplasmático/patologia , Animais , Cálcio/metabolismo , Células Cultivadas , Estresse do Retículo Endoplasmático , Técnicas de Inativação de Genes , Inativação Gênica , Coração/crescimento & desenvolvimento , Cardiopatias/metabolismo , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Humanos , Membranas Intracelulares/metabolismo , Membranas Intracelulares/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Contração Miocárdica , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Retículo Sarcoplasmático/genética , Retículo Sarcoplasmático/metabolismo , Peixe-Zebra
16.
Arch Biochem Biophys ; 683: 108299, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32061585

RESUMO

BACKGROUND: ER (endoplasmic reticulum) stress leads to decreased complex I activity in cardiac mitochondria. The aim of the current study is to explore the potential mechanisms by which ER stress leads to the complex I defect. ER stress contributes to intracellular calcium overload and oxidative stress that are two key factors to induce mitochondrial dysfunction. Since oxidative stress is often accompanied by intracellular calcium overload during ER stress in vivo, the role of oxidative stress and calcium overload in mitochondrial dysfunction was studied using in vitro models. ER stress results in intracellular calcium overload that favors activation of calcium-dependent calpains. The contribution of mitochondrial calpain activation in ER stress-mediated complex I damage was studied. METHODS: Thapsigargin (THAP) was used to induce acute ER stress in H9c2 cells and C57BL/6 mice. Exogenous calcium (25 µM) and H2O2 (100 µM) were used to induce modest calcium overload and oxidative stress in isolated mitochondria. Calpain small subunit 1 (CAPNS1) is essential to maintain calpain 1 and calpain 2 (CPN1/2) activities. Deletion of CAPNS1 eliminates the activities of CPN1/2. Wild type and cardiac-specific CAPNS1 deletion mice were used to explore the role of CPN1/2 activation in calcium-induced mitochondrial damage. RESULTS: In isolated mitochondria, exogenous calcium but not H2O2 treatment led to decreased oxidative phosphorylation, supporting that calcium overload contributes a key role in the mitochondrial damage. THAP treatment of H9c2 cells decreased respiration selectively with complex I substrates. THAP treatment activated cytosolic and mitochondrial CPN1/2 in C57BL/6 mice and led to degradation of complex I subunits including NDUFS7. Calcium treatment decreased NDUFS7 content in wild type but not in CAPNS1 knockout mice. CONCLUSION: ER stress-mediated activation of mitochondria-localized CPN1/2 contributes to complex I damage by cleaving component subunits.


Assuntos
Cálcio/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Cardiopatias/metabolismo , Mitocôndrias/metabolismo , Animais , Calpaína/metabolismo , Citosol/metabolismo , Retículo Endoplasmático/metabolismo , Deleção de Genes , Peróxido de Hidrogênio/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/metabolismo , Fosforilação Oxidativa , Estresse Oxidativo , Fosforilação , Ratos , Tapsigargina/farmacologia
17.
Cell Mol Life Sci ; 77(18): 3525-3546, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32062751

RESUMO

Over the last three decades, the scaffold proteins prohibitins-1 and -2 (PHB1/2) have emerged as key signaling proteins regulating a myriad of signaling pathways in health and diseases. Small molecules targeting PHBs display promising effects against cancers, osteoporosis, inflammatory, cardiac and neurodegenerative diseases. This review provides an updated overview of the various classes of PHB ligands, with an emphasis on their mechanism of action and therapeutic potential. We also describe how these ligands have been used to explore PHB signaling in different physiological and pathological settings.


Assuntos
Cardiopatias/patologia , Ligantes , Neoplasias/terapia , Doenças do Sistema Nervoso/terapia , Osteoporose/terapia , Proteínas Repressoras/metabolismo , Expressão Gênica , Cardiopatias/metabolismo , Cardiopatias/terapia , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/patologia , Osteoporose/metabolismo , Osteoporose/patologia , Processamento de Proteína Pós-Traducional , Proteínas Repressoras/química , Proteínas Repressoras/genética , Transdução de Sinais
19.
J Cardiovasc Pharmacol ; 75(5): 399-409, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32040034

RESUMO

3',5'-Cyclic guanosine monophosphate (cGMP) is a ubiquitous second messenger, which critically regulates cardiac pump function and protects from the development of cardiac hypertrophy by acting in various subcellular microdomains. Although clinical studies testing the potential of cGMP elevating drugs in patients suffering from cardiac disease showed promising results, deeper insight into the local actions of these drugs at the subcellular level are indispensable to inspire novel therapeutic strategies. Detailed information on the spatio-temporal dynamics of cGMP production and degradation can be provided by the use of fluorescent biosensors that are capable of monitoring this second messenger at different locations inside the cell with high temporal and spatial resolution. In this review, we will summarize how these emerging new tools have improved our understanding of cardiac cGMP signaling in health and disease, and attempt to anticipate future challenges in the field.


Assuntos
GMP Cíclico/metabolismo , Cardiopatias/metabolismo , Miocárdio/metabolismo , Sistemas do Segundo Mensageiro , Animais , Técnicas Biossensoriais , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Transferência Ressonante de Energia de Fluorescência , Guanilato Ciclase/metabolismo , Cardiopatias/fisiopatologia , Humanos , Cinética , Imagem Molecular , Diester Fosfórico Hidrolases/metabolismo
20.
Basic Res Cardiol ; 115(2): 8, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31897858

RESUMO

Macrophages are one cell type in the innate immune system. Recent studies involving macrophages have overturned the conventional concept that circulating bone marrow-derived blood mononuclear cells in the adult body continuously replace macrophages residing in the tissues. Investigations using refined technologies have suggested that embryonic hematopoiesis can result in the differentiation into macrophage subgroups in some tissues. In adulthood, these macrophages are self-sustaining via in situ proliferation, with little contribution of circulating bone marrow-derived blood mononuclear cells. Macrophages are integral component of the heart, accounting for 8% of the non-cardiac cells. The use of innovative molecular techniques in paradigm shifting researches has revealed the complexity of cardiac macrophages, including their heterogeneity and ontological diversity. Resident cardiac macrophages modulate the physiological and pathophysiological processes of the cardiovascular system, with distinct and crucial roles in healthy and injured hearts. Their functions include sensing of pathogens, antigen presentation, digesting cell debris, regulating inflammatory responses, generating distinct cytokines, and secreting some regulatory factors. More recent studies have revealed further functions of cardiac macrophages. This review focuses on macrophages within the cardiovascular system. We discuss evidence that has changed our collective view of cardiac macrophage subgroups, and improved our understanding of the different phenotypes, cell surface markers, heterogeneities, origins, developments, and the dynamic and separate roles of these cardiac macrophage subgroups in the steady state and injured hearts. This review may provide novel insights concerning the pathophysiology of cardiac-resident macrophages in cardiovascular diseases and innovative therapeutic strategies that could include the modulation of the role of macrophages in cardiovascular injuries.


Assuntos
Cardiopatias/imunologia , Imunidade Inata , Macrófagos/imunologia , Miocárdio/imunologia , Animais , Diferenciação Celular , Linhagem da Célula , Proliferação de Células , Cardiopatias/metabolismo , Cardiopatias/patologia , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Fenótipo , Transdução de Sinais
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