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1.
Artigo em Inglês | MEDLINE | ID: mdl-38957358

RESUMO

Type 2 diabetes mellitus (T2DM) is a metabolic disease and comorbidity associated with several conditions, including cardiac dysfunction leading to heart failure with preserved ejection fraction (HFpEF), in turn resulting in T2DM-induced cardiomyopathy (T2DM-CM). However, the molecular mechanisms underlying the development of T2DM-CM are poorly understood. It is hypothesized that molecular alterations in myopathic genes induced by diabetes promote the development of HFpEF, whereas cardiac myosin inhibitors can rescue the resultant T2DM-mediated cardiomyopathy. To test this hypothesis, a Leptin receptor-deficient db/db homozygous (Lepr db/db) mouse model was used to define the pathogenesis of T2DM-CM. Echocardiographic studies at 4 and 6 months revealed that Lepr db/db hearts started developing cardiac dysfunction by four months, and left ventricular hypertrophy with diastolic dysfunction was evident at 6 months. RNA-seq data analysis, followed by functional enrichment, revealed the differential regulation of genes related to cardiac dysfunction in Lepr db/db heart tissues. Strikingly, the level of cardiac myosin binding protein-C phosphorylation was significantly increased in Lepr db/db mouse hearts. Finally, using isolated skinned papillary muscles and freshly isolated cardiomyocytes, CAMZYOS ® (mavacamten, MYK-461), a prescription heart medicine used for symptomatic obstructive hypertrophic cardiomyopathy treatment, was tested for its ability to rescue T2DM-CM. Compared with controls, MYK-461 significantly reduced force generation in papillary muscle fibers and cardiomyocyte contractility in the db/db group. This line of evidence shows that 1) T2DM-CM is associated with hyperphosphorylation of cardiac myosin binding protein-C and 2) MYK-461 significantly lessened disease progression in vitro, suggesting its promise as a treatment for HFpEF.

2.
bioRxiv ; 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38746225

RESUMO

During heart failure, gene and protein expression profiles undergo extensive compensatory and pathological remodeling. We previously observed that fast skeletal myosin binding protein-C (fMyBP-C) is upregulated in diseased mouse hearts. While fMyBP-C shares significant homology with its cardiac paralog, cardiac myosin binding protein-C (cMyBP-C), there are key differences that may affect cardiac function. However, it is unknown if the expression of fMyBP-C expression in the heart is a pathological or compensatory response. We aim to elucidate the cardiac consequence of either increased or knockout of fMyBP-C expression. To determine the sufficiency of fMyBP-C to cause cardiac dysfunction, we generated cardiac-specific fMyBP-C over-expression mice. These mice were further crossed into a cMyBP-C null model to assess the effect of fMyBP-C in the heart in the complete absence of cMyBP-C. Finally, fMyBP-C null mice underwent transverse aortic constriction (TAC) to define the requirement of fMyBP-C during heart failure development. We confirmed the upregulation of fMyBP-C in several models of cardiac disease, including the use of lineage tracing. Low levels of fMyBP-C caused mild cardiac remodeling and sarcomere dysfunction. Exclusive expression of fMyBP-C in a heart failure model further exacerbated cardiac pathology. Following 8 weeks of TAC, fMyBP-C null mice demonstrated greater protection against heart failure development. Mechanistically, this may be due to the differential regulation of the myosin super-relaxed state. These findings suggest that the elevated expression of fMyBP-C in diseased hearts is a pathological response. Targeted therapies to prevent upregulation of fMyBP-C may prove beneficial in the treatment of heart failure. Significance Statement: Recently, the sarcomere - the machinery that controls heart and muscle contraction - has emerged as a central target for development of cardiac therapeutics. However, there remains much to understand about how the sarcomere is modified in response to disease. We recently discovered that a protein normally expressed in skeletal muscle, is present in the heart in certain settings of heart disease. How this skeletal muscle protein affects the function of the heart remained unknown. Using genetically engineered mouse models to modulate expression of this skeletal muscle protein, we determined that expression of this skeletal muscle protein in the heart negatively affects cardiac performance. Importantly, deletion of this protein from the heart could improve heart function suggesting a possible therapeutic avenue.

3.
PLoS One ; 18(1): e0280216, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36652449

RESUMO

Short bouts of occlusion of blood flow can induce a preconditioning response that reduces subsequent damage from longer periods of ischemia. It has been shown that ischemic preconditioning (IPC) can be elicited remotely (RIPC) through limitation of blood flow and as recently described via only pain sensation. Non-obstructive banding (NOB) through the donning of tefillin (a box with sacred texts attached to a leather strap that is traditionally bound to the non-dominant arm of Jewish adults during morning prayers) has been shown to elicit an RIPC response at least partially through pain sensation. This study evaluated the effects of NOB on heart rate variability (HRV) dependent factors that are known to be affected by various RIPC stimuli. We recruited 30 healthy subjects and subjected them to NOB versus control and found various HRV markers associated with RIPC to be changed in the NOB group. This finding provides further evidence that tefillin, likely through NOB induced RIPC changes, may still be a viable clinical pathway to prevent and decrease the morbidity associated with ischemic events.


Assuntos
Isquemia , Precondicionamento Isquêmico , Adulto , Humanos , Frequência Cardíaca , Hemodinâmica , Dor
4.
Pharmacol Res Perspect ; 11(1): e01045, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36631960

RESUMO

The recombinant monoclonal anti-cocaine antibody, h2E2, sequesters cocaine in plasma increasing concentrations more than 10-fold. The increased levels of cocaine in the plasma could have detrimental peripheral effects, particularly on the cardiovascular system. We investigated the duration and magnitude of the effect of cocaine on the rat heart, and if h2E2 could antagonize that effect. Echocardiography was used to evaluate cardiac function under isoflurane anesthesia, while a tail-cuff was used to measure blood pressure. Cocaine was delivered intravenously and the rats were continuously monitored for a total of 45 min. Echocardiography measurements were recorded every 5 min and blood pressure measurements were recorded throughout the duration of the experiment using 30-s cycles. ECG recordings were taken simultaneously with the echocardiography measurements. An increase in ejection fraction was seen after the cocaine push with the maximum change occurring at 25 min. Treatment with h2E2 1 h before the cocaine push did not have any effect on cardiac parameters. Subsequent cocaine treatment had no effect on the ejection fraction, indicating that the antibody-bound cocaine does not affect the heart. This antagonism of cocaine's effects was greatly decreased after 1 week and entirely absent after 1 month. Cocaine in the presence of h2E2 is pharmacologically inert and h2E2 may have additional clinical utility for reversing cocaine effects on the cardiovascular system.


Assuntos
Sistema Cardiovascular , Cocaína , Isoflurano , Ratos , Animais , Anticorpos , Pressão Sanguínea
5.
Front Physiol ; 12: 734113, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34867442

RESUMO

The transient receptor potential (TRP) channels have been described in almost every mammalian cell type. Several members of the Vanilloid (TRPV) subtype have been found to play important roles in modulating cardiac structure and function through Ca2+ handling in response to systemic and local mechanobiological cues. In this review, we will consider the most studied TRPV channels in the cardiovascular field; transient receptor potential vanilloid 1 as a modulator of cardiac hypertrophy; transient receptor potential vanilloid 2 as a structural and functional protein; transient receptor potential vanilloid 3 in the development of hypertrophy and myocardial fibrosis; and transient receptor potential vanilloid 4 in its roles modulating the fibrotic and functional responses of the heart to pressure overload. Lastly, we will also review the potential overlapping roles of these channels with other TRP proteins as well as the advances in translational and clinical arenas associated with TRPV channels.

6.
Cardiovasc Toxicol ; 21(11): 889-900, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34324134

RESUMO

Complete vascular occlusion to distant tissue prior to an ischemic cardiac event can provide significant cardioprotection via remote ischemic preconditioning (RIPC). Despite understanding its mechanistic basis, its translation to clinical practice has been unsuccessful, likely secondary to the inherent impossibility of predicting (and therefore preconditioning) an ischemic event, as well as the discomfort that is associated with traditional, fully occlusive RIPC stimuli. Our laboratory has previously shown that non-occlusive banding (NOB) via wrapping of a leather band (similar to a traditional Jewish ritual) can elicit an RIPC response in healthy human subjects. This study sought to further the pain-mediated aspect of this observation in a mouse model of NOB with healthy mice that were exposed to treatment with and without lidocaine to inhibit pain sensation prior to ischemia/reperfusion injury. We demonstrated that NOB downregulates key inflammatory markers resulting in a preconditioning response that is partially mediated via pain sensation.


Assuntos
Anestésicos Locais/farmacologia , Membro Anterior/irrigação sanguínea , Precondicionamento Isquêmico/métodos , Lidocaína/farmacologia , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Limiar da Dor/efeitos dos fármacos , Artéria Radial/fisiologia , Animais , Citocinas/sangue , Citocinas/genética , Modelos Animais de Doenças , Ecocardiografia , Ligadura , Masculino , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/sangue , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/diagnóstico por imagem , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Artéria Radial/diagnóstico por imagem , Fluxo Sanguíneo Regional , Fatores de Tempo
7.
Sci Rep ; 11(1): 10378, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001975

RESUMO

Congenital heart disease (CHD) is the most common congenital abnormality. A precise etiology for CHD remains elusive, but likely results from interactions between genetic and environmental factors during development, when the heart adapts to physiological and pathophysiological conditions. Further, it has become clearer that early exposure to toxins that do not result in overt CHD may be associated with adverse cardiac outcomes that are not manifested until later life. Previously, interference with endogenous developmental functions of the aryl hydrocarbon receptor (AHR), either by gene ablation or by in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent AHR ligand, was shown to cause structural, molecular and functional cardiac abnormalities and altered heart physiology in mouse embryos. Here, we show that continuous exposure to TCDD from fertilization throughout adulthood caused male mice to underperform at exercise tolerance tests compared to their control and female counterparts, confirming previous observations of a sexually dimorphic phenotype. Renin-angiotensin stimulation by angiotensin II (Ang II) caused measurable increases in blood pressure and left ventricle mass, along with decreased end diastolic volume and preserved ejection fraction. Interestingly, TCDD exposure caused measurable reductions in the myocardial hypertrophic effects of Ang II, suggesting that endogenous AHR signaling present in adulthood may play a role in the pathogenesis of hypertrophy. Overall, the findings reported in this pilot study highlight the complex systems underlying TCDD exposure in the development of cardiac dysfunction in later life.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Desenvolvimento Embrionário/efeitos dos fármacos , Cardiopatias Congênitas/genética , Coração/crescimento & desenvolvimento , Hipertrofia/genética , Receptores de Hidrocarboneto Arílico/genética , Angiotensina II/farmacologia , Animais , Dioxinas/toxicidade , Modelos Animais de Doenças , Desenvolvimento Embrionário/genética , Poluentes Ambientais/toxicidade , Feminino , Coração/efeitos dos fármacos , Coração/fisiopatologia , Cardiopatias Congênitas/induzido quimicamente , Cardiopatias Congênitas/fisiopatologia , Humanos , Hipertrofia/induzido quimicamente , Hipertrofia/fisiopatologia , Masculino , Camundongos , Condicionamento Físico Animal/efeitos adversos , Projetos Piloto , Dibenzodioxinas Policloradas/toxicidade , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/genética , Caracteres Sexuais
8.
Prog Biophys Mol Biol ; 159: 118-125, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32565182

RESUMO

The transient receptor potential (TRP) ion channel family is composed of twenty-seven channel proteins that are ubiquitously expressed in the human body. The TRPV (vanilloid) subfamily has been a recent target of investigation within the cardiovascular field. TRPV1, which is sensitive to heat as well as vanilloids, is the best characterized TRPV channel and is the namesake for the subfamily that includes six members. Research into the function of TRPV2 has suggested that it plays an important role in cardiovascular function. Over the last twenty years a greater understanding of the differences among the TRPV channels has allowed for more precise experimentation and has opened various translational opportunities. TRPV2 has been found to be a both a mechanosensor and a mediator of calcium handling and has been found to play important roles in healthy and diseased cardiomyocytes. These roles have been translated into clinical studies in patients with muscular dystrophy (both agonism and antagonism) as well as in patients with cardiomyopathy and heart failure with reduced ejection fraction. Its role as a structural protein has also been elucidated, though the clinical significance of this finding has yet to be established. Despite the clinical progress that has been made there is still a need for large, prospective randomized studies with TRPV2 channel agonists and antagonists in order to bring these basic and translational science findings to the bedside.


Assuntos
Cálcio/metabolismo , Sistema Cardiovascular/metabolismo , Distrofias Musculares/tratamento farmacológico , Miócitos Cardíacos/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Fenômenos Biomecânicos/fisiologia , Cardiomiopatias/metabolismo , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Descoberta de Drogas , Coração/fisiologia , Insuficiência Cardíaca/metabolismo , Humanos , Transdução de Sinais
9.
Toxicol Sci ; 178(2): 325-337, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33017471

RESUMO

Congenital heart disease (CHD), the leading birth defect worldwide, has a largely unknown etiology, likely to result from complex interactions between genetic and environmental factors during heart development, at a time when the heart adapts to diverse physiological and pathophysiological conditions. Crucial among these is the regulation of cardiomyocyte development and postnatal maturation, governed by dynamic changes in DNA methylation. Previous work from our laboratory has shown that exposure to the environmental toxicant tetrachlorodibenzo-p-dioxin (TCDD) disrupts several molecular networks responsible for heart development and function. To test the hypothesis that the disruption caused by TCDD in the heart results from changes in DNA methylation and gene expression patterns of cardiomyocytes, we established a stable mouse embryonic stem cell line expressing a puromycin resistance selectable marker under control of the cardiomyocyte-specific Nkx2-5 promoter. Differentiation of these cells in the presence of puromycin induces the expression of a large suite of cardiomyocyte-specific markers. To assess the consequences of TCDD treatment on gene expression and DNA methylation in these cardiomyocytes, we subjected them to transcriptome and methylome analyses in the presence of TCDD. Unlike control cardiomyocytes maintained in vehicle, the TCDD-treated cardiomyocytes showed extensive gene expression changes, with a significant correlation between differential RNA expression and DNA methylation in 111 genes, many of which are key elements of pathways that regulate cardiovascular development and function. Our findings provide an important clue toward the elucidation of the complex interactions between genetic and epigenetic mechanisms after developmental TCDD exposure that may contribute to CHD.


Assuntos
Metilação de DNA , Dioxinas/toxicidade , Células-Tronco Embrionárias/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Dibenzodioxinas Policloradas , Animais , Linhagem Celular , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Dibenzodioxinas Policloradas/toxicidade
10.
PLoS One ; 15(3): e0230386, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32218573

RESUMO

Probenecid has been used for decades in the treatment of gout but recently has also been found to improve outcomes in patients with heart failure via stimulation of the transient receptor potential vanilloid 2 (TRPV2) channel in cardiomyocytes. This study tested the use of probenecid on a novel mouse model of peripartum cardiomyopathy (PPCM) as a potential treatment option. A human mutation of the human heat shock protein 20 (Hsp20-S10F) in mice has been recently shown to result in cardiomyopathy, when exposed to pregnancies. Treatment with either probenecid or control sucrose water was initiated after the first pregnancy in both wild type and Hsp20-S10F mice. Serial echocardiography was performed during subsequent pregnancies and hearts were collected after the third pregnancies for staining and molecular analysis. Hsp20-S10F mice treated with probenecid had decreased mortality, hypertrophy, TRPV2 expression and molecular parameters of heart failure. Probenecid treatment also decreased apoptosis as evidenced by an increase in the level of Bcl-2/Bax. Probenecid improved survival in a novel mouse model of PPCM and may be an appropriate therapy for humans with PPCM as it has a proven safety and tolerability in patients with heart failure.


Assuntos
Canais de Cálcio/genética , Cardiomiopatias/tratamento farmacológico , Proteínas de Choque Térmico HSP20/genética , Insuficiência Cardíaca/tratamento farmacológico , Probenecid/farmacologia , Canais de Cátion TRPV/genética , Animais , Apoptose/efeitos dos fármacos , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/genética , Cardiomiopatias/patologia , Modelos Animais de Doenças , Ecocardiografia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Humanos , Camundongos , Mutação/genética , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Período Periparto/efeitos dos fármacos , Gravidez , Complicações Cardiovasculares na Gravidez/tratamento farmacológico , Complicações Cardiovasculares na Gravidez/genética
11.
Skelet Muscle ; 9(1): 4, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30678732

RESUMO

BACKGROUND: Skeletal muscle myopathy and exercise intolerance are diagnostic hallmarks of heart failure (HF). However, the molecular adaptations of skeletal muscles during dilated cardiomyopathy (DCM)-mediated HF are not completely understood. METHODS: Skeletal muscle structure and function were compared in wild-type (WT) and cardiac myosin binding protein-C null mice (t/t), which develop DCM-induced HF. Cardiac function was examined by echocardiography. Exercise tolerance was measured using a graded maximum treadmill running test. Hindlimb muscle function was assessed in vivo from measurements of plantar flexor strength. Inflammatory status was evaluated from the expression of inflammatory markers and the presence of specific immune cell types in gastrocnemius muscles. Muscle regenerative capacityat days 3, 7, and 14 after eccentric contraction-induced injury was determined from the number of phenotypically new and adult fibers in the gastrocnemius, and functional recovery of plantar flexion torque. RESULTS: t/t mice developed DCM-induced HF in association with profound exercise intolerance, consistent with previous reports. Compared to WT, t/t mouse hearts show significant hypertrophy of the atria and ventricles and reduced fractional shortening, both systolic and diastolic. In parallel, the skeletal muscles of t/t mice exhibit weakness and myopathy. Compared to WT, plantar flexor muscles of t/t null mice produce less peak isometric plantar torque (Po), develop torque more slowly (+ dF/dt), and relax more slowly (- dF/dt, longer half-relaxation times,1/2RT). Gastrocnemius muscles of t/t mice have a greater number of fibers with smaller diameters and central nuclei. Oxidative fibers, both type I and type IIa, show significantly smaller cross-sectional areas and more central nuclei. These fiber phenotypes suggest ongoing repair and regeneration under homeostatic conditions. In addition, the ability of muscles to recover and regenerate after acute injury is impaired in t/t mice. CONCLUSIONS: Our studies concluded that DCM-induced HF induces a unique skeletal myopathy characterized by decreased muscle strength, atrophy of oxidative fiber types, ongoing inflammation and damage under homeostasis, and impaired regeneration after acute muscle injury. Furthermore, this unique myopathy in DCM-induced HF likely contributes to and exacerbates exercise intolerance. Therefore, efforts to develop therapeutic interventions to treat skeletal myopathy during DCM-induced HF should be considered.


Assuntos
Cardiomiopatia Dilatada/complicações , Insuficiência Cardíaca/fisiopatologia , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Doenças Musculares/metabolismo , Miosite/metabolismo , Animais , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/patologia , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Knockout , Força Muscular , Doenças Musculares/etiologia , Miosite/etiologia , Condicionamento Físico Animal , Regeneração
12.
J Appl Toxicol ; 39(4): 603-621, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30561030

RESUMO

Polychlorinated biphenyls (PCBs) are toxic environmental pollutants. Humans are exposed to PCB mixtures via contaminated food or water. PCB exposure causes adverse effects in adults and after exposure in utero. PCB toxicity depends on the congener mixture and CYP1A2 gene activity. For coplanar PCBs, toxicity depends on ligand affinity for the aryl hydrocarbon receptor (AHR). Previously, we found that perinatal exposure of mice to a three-coplanar/five-noncoplanar PCB mixture induced deficits in novel object recognition and trial failures in the Morris water maze in Cyp1a2-/- ::Ahrb1 C57BL6/J mice compared with wild-type mice (Ahrb1  = high AHR affinity). Here we exposed gravid Cyp1a2-/- ::Ahrb1 mice to a PCB mixture on embryonic day 10.5 by gavage and examined the F1 and F3 offspring (not F2 ). PCB-exposed F1 mice exhibited increased open-field central time, reduced acoustic startle, greater conditioned contextual freezing and reduced CA1 hippocampal long-term potentiation with no change in spatial learning or memory. F1 mice also had inhibited growth, decreased heart rate and cardiac output, and impaired fertility. F3 mice showed few effects. Gene expression changes were primarily in F1 PCB males compared with wild-type males. There were minimal RNA and DNA methylation changes in the hippocampus from F1 to F3 with no clear relevance to the functional effects. F0 PCB exposure during a period of rapid DNA de-/remethylation in a susceptible genotype produced clear F1 effects with little evidence of transgenerational effects in the F3 generation. While PCBs show clear developmental neurotoxicity, their effects do not persist across generations for effects assessed herein.


Assuntos
Citocromo P-450 CYP1A2/metabolismo , Poluentes Ambientais/toxicidade , Fertilidade/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Bifenilos Policlorados/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Reflexo de Sobressalto/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Animais , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/fisiopatologia , Condicionamento Clássico , Citocromo P-450 CYP1A2/genética , Feminino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/enzimologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/psicologia
13.
J Cardiovasc Pharmacol ; 72(1): 40-48, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29688911

RESUMO

Tranilast is clinically indicated for the treatment of allergic disorders and is also a nonselective blocker of the transient receptor potential vanilloid 2 (TRPV2) channel. Previous studies have found that it has protective effects in various animal models of cardiac disease. Our laboratory has found that genetic deletion of TRPV2 results in a blunted hypertrophic response to increased afterload; thus, this study tested the hypothesis that tranilast through cardiomyocyte TRPV2 blockade can inhibit the hypertrophic response to pressure overload in vivo through transverse aortic constriction and ex vivo through isolated myocyte studies. The in vivo studies demonstrated that tranilast blunted the fibrotic response to increased afterload and, to a lesser extent, the hypertrophic response. After 4 weeks, this blunting was associated with improved cardiac function, although at 8 weeks, the cardiac function deteriorated similarly to the control group. Finally, the in vitro studies demonstrated that tranilast was not inhibiting these responses at the cardiomyocyte level. In conclusion, we demonstrated that tranilast blunting of the fibrotic and hypertrophic response occurs independently of cardiac TRPV2 channels and may be cardioprotective in the short term but not after prolonged administration.


Assuntos
Hipertrofia Ventricular Esquerda/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Canais de Cátion TRPV/antagonistas & inibidores , Disfunção Ventricular Esquerda/prevenção & controle , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , ortoaminobenzoatos/farmacologia , Animais , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Fibrose , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Recuperação de Função Fisiológica , Transdução de Sinais/efeitos dos fármacos , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Fatores de Tempo , Fator de Crescimento Transformador beta1/metabolismo , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , ortoaminobenzoatos/toxicidade
14.
J Am Heart Assoc ; 7(2)2018 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-29331959

RESUMO

BACKGROUND: Transient receptor potential vanilloid 2 is a calcium channel activated by probenecid. Probenecid is a Food and Drug Administration-approved uricosuric drug that has recently been shown to induce positive lusitropic and inotropic effects in animal models through cardiomyocyte transient receptor potential vanilloid 2 activation. The aim of this study was to test the hypothesis that oral probenecid can improve cardiac function and symptomatology in patients with heart failure with reduced ejection fraction and to further elucidate its calcium-dependent effects on myocyte contractility. METHODS AND RESULTS: The clinical trial recruited stable outpatients with heart failure with reduced ejection fraction randomized in a single-center, double-blind, crossover design. Clinical data were collected including a dyspnea assessment, physical examination, ECG, echocardiogram to assess systolic and diastolic function, a 6-minute walk test, and laboratory studies. In vitro force generation studies were performed on cardiomyocytes isolated from murine tissue exposed to probenecid or control treatments. The clinical trial recruited 20 subjects (mean age 57 years, mean baseline fractional shortening of 13.6±1.0%). Probenecid therapy increased fractional shortening by 2.1±1.0% compared with placebo -1.7±1.0% (P=0.007). Additionally, probenecid improved diastolic function compared with placebo by decreasing the E/E' by -2.95±1.21 versus 1.32±1.21 in comparison to placebo (P=0.03). In vitro probenecid increased myofilament force generation (92.36 versus 80.82 mN/mm2, P<0.05) and calcium sensitivity (pCa 5.67 versus 5.60, P<0.01) compared with control. CONCLUSIONS: Probenecid improves cardiac function with minimal effects on symptomatology and no significant adverse effects after 1 week in patients with heart failure with reduced ejection fraction and increases force development and calcium sensitivity at the cardiomyocyte level. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01814319.


Assuntos
Sinalização do Cálcio/efeitos dos fármacos , Cardiotônicos/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Probenecid/administração & dosagem , Volume Sistólico/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos , Administração Oral , Animais , Cardiotônicos/efeitos adversos , Estudos Cross-Over , Método Duplo-Cego , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Miócitos Cardíacos/metabolismo , Ohio , Probenecid/efeitos adversos , Recuperação de Função Fisiológica , Fatores de Tempo , Resultado do Tratamento
15.
Mol Cancer Ther ; 16(11): 2432-2441, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28864682

RESUMO

Inhibition of mTOR signaling using the rapalog everolimus is an FDA-approved targeted therapy for patients with lung and gastroenteropancreatic neuroendocrine tumors (NET). However, patients eventually progress on treatment, highlighting the need for additional therapies. We focused on pancreatic NETs (pNET) and reasoned that treatment of these tumors upon progression on rapalog therapy, with an mTOR kinase inhibitor (mTORKi), such as CC-223, could overcome a number of resistance mechanisms in tumors and delay cardiac carcinoid disease. We performed preclinical studies using human pNET cells in vitro and injected them subcutaneously or orthotopically to determine tumor progression and cardiac function in mice treated with either rapamycin alone or switched to CC-223 upon progression. Detailed signaling and RNA sequencing analyses were performed on tumors that were sensitive or progressed on mTOR treatment. Approximately 57% of mice bearing pNET tumors that progressed on rapalog therapy showed a significant decrease in tumor volume upon a switch to CC-223. Moreover, mice treated with an mTORKi exhibited decreased cardiac dilation and thickening of heart valves than those treated with placebo or rapamycin alone. In conclusion, in the majority of pNETs that progress on rapalogs, it is possible to reduce disease progression using an mTORKi, such as CC-223. Moreover, CC-223 had an additional transient cardiac benefit on valvular fibrosis compared with placebo- or rapalog-treated mice. These results provide the preclinical rationale to further develop mTORKi clinically upon progression on rapalog therapy and to further test their long-term cardioprotective benefit in those NET patients prone to carcinoid syndrome. Mol Cancer Ther; 16(11); 2432-41. ©2017 AACR.


Assuntos
Doença Cardíaca Carcinoide/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Serina-Treonina Quinases TOR/genética , Animais , Doença Cardíaca Carcinoide/complicações , Doença Cardíaca Carcinoide/genética , Doença Cardíaca Carcinoide/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Everolimo/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Tumores Neuroendócrinos/complicações , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Pirazinas/administração & dosagem , Sirolimo/administração & dosagem , Serina-Treonina Quinases TOR/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Aging Clin Exp Res ; 29(5): 863-873, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27804106

RESUMO

BACKGROUND: The aging heart is characterized by cellular and molecular changes leading to a decline in physiologic function and cardiac remodeling, specifically the development of myocyte hypertrophy and fibrosis. Transient receptor potential vanilloid 2 (TRPV2), a stretch-mediated channel and regulator of calcium homeostasis, plays a key role in the function and structure of the heart. TRPV2 also plays an important role in the adaptive and maladaptive compensatory mechanisms of the heart in response to pathologic and exercise-induced stress. Our current study seeks to elucidate the potential role of TRPV2 channels in the regulation of cardiac function in aging. METHODS: Wild-type (WT) and TRPV2 functional knockout (FKO) mice were aged out to various time points, and their cardiac function was measured using advanced echocardiography. Furthermore, we histologically analyzed the heart morphology to determine myocyte hypertrophy, the development of fibrosis and the relative expression of TRPV2. RESULTS: Our results demonstrate that even though TRPV2-FKO mice have impaired function at baseline, their cardiac function as measured via standard and advanced echocardiographic parameters (ejection fraction, cardiac output and circumferential strain) decreased less with aging in comparison with the WT group. Furthermore, there was less fibrosis and hypertrophy in the TRPV2-FKO group with aging in comparison with the WT. The expression of TRPV2 in the WT group did not significantly change with aging. CONCLUSIONS: TRPV2 functional deletion is compatible with aging and associated with a decreased development of myocyte hypertrophy and fibrosis. It may be an important target for prevention of age-induced cardiac remodeling.


Assuntos
Ecocardiografia/métodos , Coração/fisiopatologia , Canais de Cátion TRPV/genética , Animais , Feminino , Fibrose , Masculino , Camundongos , Camundongos Knockout
17.
J Hypertens ; 35(3): 602-611, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28009703

RESUMO

OBJECTIVE: Hypertension (increased afterload) results in cardiomyocyte hypertrophy leading to left ventricular hypertrophy and subsequently, heart failure with preserved ejection fraction. This study was performed to test the hypothesis that transient receptor potential vanilloid 2 subtype (TRPV2) function regulates hypertrophy under increased afterload conditions. METHODS: We used functional (pore specific) TRPV2 knockout mice to evaluate the effects of increased afterload-induced stretch on cardiac size and function via transverse aortic constriction (TAC) as well as hypertrophic stimuli including adrenergic and angiotensin stimulation via subcutaneous pumps. Wild-type animals served as control for all experiments. Expression and localization of TRPV2 was investigated in wild-type cardiac samples. Changes in cardiac function were measured in vivo via echocardiography and invasive catheterization. Molecular changes, including protein and real-time PCR markers of hypertrophy, were measured in addition to myocyte size. RESULTS: TRPV2 is significantly upregulated in wild-type mice after TAC, though not in response to beta-adrenergic or angiotensin stimulation. TAC-induced stretch stimulus caused an upregulation of TRPV2 in the sarcolemmal membrane. The absence of functional TRPV2 resulted in significantly reduced left ventricular hypertrophy after TAC, though not in response to beta-adrenergic or angiotensin stimulation. The decreased development of hypertrophy was not associated with significant deterioration of cardiac function. CONCLUSION: We conclude that TRPV2 function, as a stretch-activated channel, regulates the development of cardiomyocyte hypertrophy in response to increased afterload.


Assuntos
Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Coração/fisiopatologia , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/etiologia , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Angiotensina II/farmacologia , Animais , Aorta/patologia , Aorta/cirurgia , Constrição Patológica/complicações , Constrição Patológica/fisiopatologia , Ecocardiografia , Insuficiência Cardíaca/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Isoproterenol/farmacologia , Masculino , Camundongos , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Sarcolema/metabolismo , Regulação para Cima/efeitos dos fármacos , Vasoconstritores/farmacologia
18.
PLoS One ; 10(9): e0136901, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26356305

RESUMO

The myocardial response to exercise is an adaptive mechanism that permits the heart to maintain cardiac output via improved cardiac function and development of hypertrophy. There are many overlapping mechanisms via which this occurs with calcium handling being a crucial component of this process. Our laboratory has previously found that the stretch sensitive TRPV2 channels are active regulators of calcium handling and cardiac function under baseline conditions based on our observations that TRPV2-KO mice have impaired cardiac function at baseline. The focus of this study was to determine the cardiac function of TRPV2-KO mice under exercise conditions. We measured skeletal muscle at baseline in WT and TRPV2-KO mice and subjected them to various exercise protocols and measured the cardiac response using echocardiography and molecular markers. Our results demonstrate that the TRPV2-KO mouse did not tolerate forced exercise although they became increasingly exercise tolerant with voluntary exercise. This occurs as the cardiac function deteriorates further with exercise. Thus, our conclusion is that TRPV2-KO mice have impaired cardiac functional response to exercise.


Assuntos
Canais de Cálcio/metabolismo , Miocárdio/metabolismo , Condicionamento Físico Animal , Canais de Cátion TRPV/metabolismo , Animais , Western Blotting , Canais de Cálcio/genética , Eletrocardiografia , Regulação da Expressão Gênica , Imuno-Histoquímica , Masculino , Camundongos Knockout , Contração Miocárdica , Reação em Cadeia da Polimerase em Tempo Real , Estresse Fisiológico , Canais de Cátion TRPV/genética
19.
Am J Physiol Heart Circ Physiol ; 307(12): H1705-13, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25239807

RESUMO

Previous studies have demonstrated improvement of cardiac function occurs with acute consumption of a high-fat diet (HFD) after myocardial infarction (MI). However, no data exist addressing the effects of acute HFD upon the extent of injury after MI. This study investigates the hypothesis that short-term HFD, prior to infarction, protects the heart against ischemia-reperfusion (I/R) injury through NF-κB-dependent regulation of cell death pathways in the heart. Data show that an acute HFD initiates cardioprotection against MI (>50% reduction in infarct size normalized to risk region) after 24 h to 2 wk of HFD, but protection is completely absent after 6 wk of HFD, when mice are reported to develop pathophysiology related to the diet. Furthermore, cardioprotection after 24 h of HFD persists after an additional 24 h of normal chow feeding and was found to be dependent upon NF-κB activation in cardiomyocytes. This study also indicates that short-term HFD activates autophagic processes (beclin-1, LC-3) preischemia, as seen in other protective stimuli. Increases in beclin-1 and LC-3 were found to be NF-κB-dependent, and administration of chloroquine, an inhibitor of autophagy, abrogated cardioprotection. Our results support that acute high-fat feeding mediates cardioprotection against I/R injury associated with a NF-κB-dependent increase in autophagy and reduced apoptosis, as has been found for ischemic preconditioning.


Assuntos
Autofagia , Dieta Hiperlipídica , Traumatismo por Reperfusão Miocárdica/dietoterapia , NF-kappa B/metabolismo , Animais , Apoptose , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteína Beclina-1 , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/metabolismo , NF-kappa B/genética
20.
Cardiovasc Pathol ; 23(6): 327-34, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25035060

RESUMO

The cardiac regenerative capacity of MRL/MpJ mouse remains a controversy. Although the MRL mouse has been reported to exhibit minimal scarring and subsequent cardiac regeneration after cryoinjury of the right ventricle, multiple studies have been unable to replicate this cardiac regenerative capacity after both cryogenic and coronary ligation cardiac injury. Therefore, we evaluated the cardiac regenerative wound-healing response and functional recovery of MRL mice compared to C57 mice, in response to a clinically relevant left ventricular (LV) coronary ligation. Male MRL/MpJ+/+ and C57BL/6 mice underwent left coronary artery ligation followed by reperfusion. Cardiac function was evaluated by echocardiography [LV ejection fraction (LVEF), LV end-diastolic volume (LVEDV), LV mass, wall thickness] at 24 hours post-ischemia and weekly for 13 weeks thereafter. Hearts were also analyzed histologically for individual cardiomyocyte hypertrophy and cardiac fibrosis. Our results show that contrary to prior reports of cardiac regenerations, MRL mice progress to heart failure more rapidly following I/R injury as marked by a significant decrease in LVEF, increase in LVEDV, LV mass, individual myocyte size, and fibrosis in the post-ischemic myocardium. Therefore, we conclude that MRL mice do not exhibit regeneration of the LV or enhanced functional improvement in response to coronary ligation. However, unlike prior studies, we matched initial infarct size in MRL and C57 mice, used high frequency echocardiography, and histological analysis to reach this conclusion. The prospect of cardiac regeneration after ischemia in MRL mice seems to have attenuated interest, given the multiple negative studies and the promise of stem cell cardiac regeneration. However, our novel observation that MRL may possess an impaired compensated hypertrophy response makes the MRL mouse strain an interesting model in the study of cardiac hypertrophy.


Assuntos
Insuficiência Cardíaca/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Animais , Crescimento Celular , Progressão da Doença , Fibrose , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Hipertrofia Ventricular Esquerda/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Modelos Cardiovasculares , Traumatismo por Reperfusão Miocárdica/complicações , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miócitos Cardíacos/patologia , Regeneração , Células-Tronco/patologia , Função Ventricular Esquerda , Remodelação Ventricular
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