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1.
Nano Energy ; 90(Pt A)2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34737918

RESUMO

Implantable nanogenerators (i-NG) provide power to cardiovascular implantable electronic devices (CIEDs) by harvesting biomechanical energy locally eliminating the need for batteries. However, its long-term operation and biological influences on the heart have not been tested. Here, we evaluate a soft and flexible i-NG system engineered for long-term in vivo cardiac implantation. It consisted of i-NG, leads, and receivers, and was implanted on the epicardium of swine hearts for 2 months. The i-NG system generated electric current throughout the testing period. Biocompatibility and biosafety were established based on normal blood and serum test results and no tissue reactions. Heart function was unchanged over the testing period as validated by normal electrocardiogram (ECG), transthoracic ultrasound, and invasive cardiac functional measures. This research demonstrates the safety, long term operation and therefore the feasibility of using i-NGs to power the next generation CIEDs.

2.
Science ; 373(6552): 337-342, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34437153

RESUMO

Piezoelectric biomaterials are intrinsically suitable for coupling mechanical and electrical energy in biological systems to achieve in vivo real-time sensing, actuation, and electricity generation. However, the inability to synthesize and align the piezoelectric phase at a large scale remains a roadblock toward practical applications. We present a wafer-scale approach to creating piezoelectric biomaterial thin films based on γ-glycine crystals. The thin film has a sandwich structure, where a crystalline glycine layer self-assembles and automatically aligns between two polyvinyl alcohol (PVA) thin films. The heterostructured glycine-PVA films exhibit piezoelectric coefficients of 5.3 picocoulombs per newton or 157.5 × 10-3 volt meters per newton and nearly an order of magnitude enhancement of the mechanical flexibility compared with pure glycine crystals. With its natural compatibility and degradability in physiological environments, glycine-PVA films may enable the development of transient implantable electromechanical devices.


Assuntos
Materiais Biocompatíveis/química , Eletricidade , Glicina/química , Álcool de Polivinil/química , Animais , Sobrevivência Celular , Células Cultivadas , Cristalização , Teoria da Densidade Funcional , Elasticidade , Humanos , Ligação de Hidrogênio , Próteses e Implantes , Ratos , Ratos Sprague-Dawley , Estresse Mecânico
3.
Nat Aging ; 1(1): 73-86, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33796866

RESUMO

Protein restricted (PR) diets promote health and longevity in many species. While the precise components of a PR diet that mediate the beneficial effects to longevity have not been defined, we recently showed that many metabolic effects of PR can be attributed to reduced dietary levels of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine. Here, we demonstrate that restricting dietary BCAAs increases the survival of two different progeroid mouse models, delays frailty and promotes the metabolic health of wild-type C57BL/6J mice when started in midlife, and leads to a 30% increase in lifespan and a reduction in frailty in male, but not female, wild-type mice when fed lifelong. Our results demonstrate that restricting dietary BCAAs can increase healthspan and longevity in mice, and suggest that reducing dietary BCAAs may hold potential as a translatable intervention to promote healthy aging.

4.
J Gen Physiol ; 153(7)2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-33646280

RESUMO

The Frank-Starling relationship establishes that elevated end-diastolic volume progressively increases ventricular pressure and stroke volume in healthy hearts. The relationship is modulated by a number of physiological inputs and is often depressed in human heart failure. Emerging evidence suggests that cardiac myosin-binding protein-C (cMyBP-C) contributes to the Frank-Starling relationship. We measured contractile properties at multiple levels of structural organization to determine the role of cMyBP-C and its phosphorylation in regulating (1) the sarcomere length dependence of power in cardiac myofilaments and (2) the Frank-Starling relationship in vivo. We compared transgenic mice expressing wild-type cMyBP-C on the null background, which have ∼50% phosphorylated cMyBP-C (Controls), to transgenic mice lacking cMyBP-C (KO) and to mice expressing cMyBP-C that have serine-273, -282, and -302 mutated to aspartate (cMyBP-C t3SD) or alanine (cMyBP-C t3SA) on the null background to mimic either constitutive PKA phosphorylation or nonphosphorylated cMyBP-C, respectively. We observed a continuum of length dependence of power output in myocyte preparations. Sarcomere length dependence of power progressively increased with a rank ordering of cMyBP-C KO = cMyBP-C t3SA < Control < cMyBP-C t3SD. Length dependence of myofilament power translated, at least in part, to hearts, whereby Frank-Starling relationships were steepest in cMyBP-C t3SD mice. The results support the hypothesis that cMyBP-C and its phosphorylation state tune sarcomere length dependence of myofibrillar power, and these regulatory processes translate across spatial levels of myocardial organization to control beat-to-beat ventricular performance.


Assuntos
Estorninhos , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Camundongos , Camundongos Transgênicos , Contração Miocárdica , Miocárdio/metabolismo , Fosforilação , Sarcômeros/metabolismo , Estorninhos/metabolismo
5.
Circulation ; 143(20): 1973-1986, 2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-33666092

RESUMO

BACKGROUND: Neonatal mouse cardiomyocytes undergo a metabolic switch from glycolysis to oxidative phosphorylation, which results in a significant increase in reactive oxygen species production that induces DNA damage. These cellular changes contribute to cardiomyocyte cell cycle exit and loss of the capacity for cardiac regeneration. The mechanisms that regulate this metabolic switch and the increase in reactive oxygen species production have been relatively unexplored. Current evidence suggests that elevated reactive oxygen species production in ischemic tissues occurs as a result of accumulation of the mitochondrial metabolite succinate during ischemia via succinate dehydrogenase (SDH), and this succinate is rapidly oxidized at reperfusion. Mutations in SDH in familial cancer syndromes have been demonstrated to promote a metabolic shift into glycolytic metabolism, suggesting a potential role for SDH in regulating cellular metabolism. Whether succinate and SDH regulate cardiomyocyte cell cycle activity and the cardiac metabolic state remains unclear. METHODS: Here, we investigated the role of succinate and SDH inhibition in regulation of postnatal cardiomyocyte cell cycle activity and heart regeneration. RESULTS: Our results demonstrate that injection of succinate into neonatal mice results in inhibition of cardiomyocyte proliferation and regeneration. Our evidence also shows that inhibition of SDH by malonate treatment after birth extends the window of cardiomyocyte proliferation and regeneration in juvenile mice. Remarkably, extending malonate treatment to the adult mouse heart after myocardial infarction injury results in a robust regenerative response within 4 weeks after injury via promoting adult cardiomyocyte proliferation and revascularization. Our metabolite analysis after SDH inhibition by malonate induces dynamic changes in adult cardiac metabolism. CONCLUSIONS: Inhibition of SDH by malonate promotes adult cardiomyocyte proliferation, revascularization, and heart regeneration via metabolic reprogramming. These findings support a potentially important new therapeutic approach for human heart failure.

6.
J Pediatr Intensive Care ; 10(1): 31-37, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33585059

RESUMO

The aim of this study was to examine the use of volumetric capnography monitoring to assess cardiopulmonary resuscitation (CPR) effectiveness by correlating it with cardiac output (CO), and to evaluate the effect of epinephrine boluses on both end-tidal carbon dioxide (EtCO 2 ) and the volume of CO 2 elimination (VCO 2 ) in a swine ventricular fibrillation cardiac arrest model. Planned secondary analysis of data collected to investigate the use of noninvasive monitors in a pediatric swine ventricular fibrillation cardiac arrest model was performed. Twenty-eight ventricular fibrillatory arrests with open cardiac massage were conducted. During CPR, EtCO 2 and VCO 2 had strong correlation with CO, measured as a percentage of baseline pulmonary blood flow, with correlation coefficients of 0.83 ( p < 0.001) and 0.53 ( p = 0.018), respectively. However, both EtCO 2 and VCO 2 had weak and nonsignificant correlation with diastolic blood pressure during CPR 0.30 ( p = 0.484) (95% confidence interval [CI], -0.51-0.83) and 0.25 ( p = 0.566) (95% CI, -0.55-0.81), respectively. EtCO 2 and VCO 2 increased significantly after the first epinephrine bolus without significant change in CO. The correlations between EtCO 2 and VCO 2 and CO were weak 0.20 ( p = 0.646) (95% CI, -0.59-0.79), and 0.27 ( p = 0.543) (95% CI, -0.54-0.82) following epinephrine boluses. Continuous EtCO 2 and VCO 2 monitoring are potentially useful metrics to ensure effective CPR. However, transient epinephrine administration by boluses might confound the use of EtCO 2 and VCO 2 to guide chest compression.

7.
J Biomech Eng ; 143(3)2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33175151

RESUMO

Sickle cell disease (SCD) is a hereditary blood disorder affecting millions of people in which red blood cells (RBCs) become sickled and lyse easily driven by polymerization of hemoglobin. Chronically, SCD causes anemia and biventricular dysfunction. GBT440 is an experimental treatment for SCD that prevents hemoglobin polymerization. We hypothesized that 17-month-old Berkeley SCD mice treated with GBT440 would have increased hematocrit (Hct) and better biventricular function compared to vehicle treated SCD mice. Our results demonstrate that 3 weeks of GBT440 treatment eliminated chronic anemia, increased left ventricular ejection fraction (LVEF) and stroke volume index, and improved right ventricular function. Overall, our findings support a therapeutic effect of GBT440 in vivo in a small animal model of SCD. Next steps in investigating mechanisms of improved cardiac function are warranted.

8.
Am J Physiol Heart Circ Physiol ; 319(6): H1459-H1473, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33064565

RESUMO

Although women are more susceptible to pulmonary arterial hypertension (PAH) than men, their right ventricular (RV) function is better preserved. Estrogen receptor-α (ERα) has been identified as a likely mediator for estrogen protection in the RV. However, the role of ERα in preserving RV function and remodeling during pressure overload remains poorly understood. We hypothesized that loss of functional ERα removes female protection from adverse remodeling and is permissive for the development of a maladapted RV phenotype. Male and female rats with a loss-of-function mutation in ERα (ERαMut) and wild-type (WT) littermates underwent RV pressure overload by pulmonary artery banding (PAB). At 10 wk post-PAB, WT and ERαMut demonstrated RV hypertrophy. Analysis of RV pressure waveforms demonstrated RV-pulmonary vascular uncoupling and diastolic dysfunction in female, but not male, ERαMut PAB rats. Similarly, female, but not male, ERαMut exhibited increased RV fibrosis, comprised primarily of thick collagen fibers. There was an increased protein expression ratio of TIMP metallopeptidase inhibitor 1 (Timp1) to matrix metalloproteinase 9 (Mmp9) in female ERαMut compared with WT PAB rats, suggesting less collagen degradation. RNA-sequencing in female WT and ERαMut RV revealed kallikrein-related peptidase 10 (Klk10) and Jun Proto-Oncogene (Jun) as possible mediators of female RV protection during PAB. In summary, ERα in females is protective against RV-pulmonary vascular uncoupling, diastolic dysfunction, and fibrosis in response to pressure overload. ERα appears to be dispensable for RV adaptation in males. ERα may be a mediator of superior RV adaptation in female patients with PAH.NEW & NOTEWORTHY Using a novel loss-of-function mutation in estrogen receptor-α (ERα), we demonstrate that female, but not male, ERα mutant rats display right ventricular (RV)-vascular uncoupling, diastolic dysfunction, and fibrosis following pressure overload, indicating a sex-dependent role of ERα in protecting against adverse RV remodeling. TIMP metallopeptidase inhibitor 1 (Timp1), matrix metalloproteinase 9 (Mmp9), kallikrein-related peptidase 10 (Klk10), and Jun Proto-Oncogene (Jun) were identified as potential mediators in ERα-regulated pathways in RV pressure overload.


Assuntos
Receptor alfa de Estrogênio/metabolismo , Hipertrofia Ventricular Direita/prevenção & controle , Miocárdio/metabolismo , Disfunção Ventricular Direita/prevenção & controle , Função Ventricular Direita , Remodelação Ventricular , Animais , Modelos Animais de Doenças , Receptor alfa de Estrogênio/genética , Feminino , Colágenos Fibrilares/metabolismo , Fibrose , Hipertrofia Ventricular Direita/metabolismo , Hipertrofia Ventricular Direita/patologia , Hipertrofia Ventricular Direita/fisiopatologia , Calicreínas/genética , Calicreínas/metabolismo , Masculino , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Mutação , Miocárdio/patologia , Proteínas Proto-Oncogênicas c-jun/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , Ratos Mutantes , Ratos Sprague-Dawley , Fatores Sexuais , Transdução de Sinais , Disfunção Ventricular Direita/metabolismo , Disfunção Ventricular Direita/patologia , Disfunção Ventricular Direita/fisiopatologia
9.
Sci Adv ; 6(27)2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32937431

RESUMO

Nonviral mRNA delivery is an attractive therapeutic gene delivery strategy, as it achieves efficient protein overexpression in vivo and has a desirable safety profile. However, mRNA's short cytoplasmic half-life limits its utility to therapeutic applications amenable to repeated dosing or short-term overexpression. Here, we describe a biomaterial that enables a durable in vivo response to a single mRNA dose via an "overexpress and sequester" mechanism, whereby mRNA-transfected cells locally overexpress a growth factor that is then sequestered within the biomaterial to sustain the biologic response over time. In a murine diabetic wound model, this strategy demonstrated improved wound healing compared to delivery of a single mRNA dose alone or recombinant protein. In addition, codelivery of anti-inflammatory proteins using this biomaterial eliminated the need for mRNA chemical modification for in vivo therapeutic efficacy. The results support an approach that may be broadly applicable for single-dose delivery of mRNA without chemical modification.

10.
J Clin Monit Comput ; 34(1): 63-70, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30820870

RESUMO

ABSTARCT: To investigate the use of two-site regional oxygen saturations (rSO2) and end tidal carbon dioxide (EtCO2) to assess the effectiveness of resuscitation and return of spontaneous circulation (ROSC). Eight mechanically ventilated juvenile swine underwent 28 ventricular fibrillatory arrests with open cardiac massage. Cardiac massage was administered to achieve target pulmonary blood flow (PBF) as a percentage of pre-cardiac arrest baseline. Non-invasive data, including, EtCO2, cerebral rSO2 (C-rSO2) and renal rSO2 (R-rSO2) were collected continuously. Our data demonstrate the ability to measure both rSO2 and EtCO2 during CPR and after ROSC. During resuscitation EtCO2 had a strong correlation with goal CO with r = 0.83 (p < 0.001) 95% CI [0.67-0.92]. Both C-rSO2 and R-rSO2 had moderate and statistically significant correlation with CO with r = 0.52 (p = 0.003) 95% CI (0.19-0.74) and 0.50 (p = 0.004) 95% CI [0.16-0.73]. The AUCs for sudden increase of EtCO2, C-rSO2, and R-rSO2 at ROSC were 0.86 [95% CI, 0.77-0.94], 0.87 [95% CI, 0.8-0.94], and 0.98 [95% CI, 0.96-1.00] respectively. Measurement of continuous EtCO2 and rSO2 may be used during CPR to ensure effective chest compressions. Moreover, both rSO2 and EtCO2 may be used to detect ROSC in a swine pediatric ventricular fibrillatory arrest model.


Assuntos
Capnografia/métodos , Parada Cardíaca/terapia , Oxigênio/metabolismo , Ressuscitação/métodos , Fibrilação Ventricular , Animais , Dióxido de Carbono , Reanimação Cardiopulmonar , Circulação Cerebrovascular/fisiologia , Modelos Animais de Doenças , Parada Cardíaca/fisiopatologia , Hemodinâmica , Monitorização Fisiológica , Oximetria , Curva ROC , Espectroscopia de Luz Próxima ao Infravermelho , Estresse Mecânico , Suínos
12.
Am J Physiol Heart Circ Physiol ; 317(6): H1272-H1281, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31702968

RESUMO

Rats exposed to postnatal hyperoxia develop right ventricular (RV) dysfunction, mild pulmonary hypertension, and dysregulated cardiac mitochondrial biogenesis when aged to one year, with the degree of cardiac dysfunction and pulmonary hypertension similar to that previously described in young adults born preterm. Here, we sought to understand the impact of postnatal hyperoxia exposure on RV hemodynamic and mitochondrial function across the life span. In Methods, pups from timed-pregnant Sprague-Dawley rats were randomized to normoxia or hyperoxia [fraction of inspired oxygen (FIO2), 0.85] exposure for the first 14 days of life, a commonly used model of chronic lung disease of prematurity. RV hemodynamic and mitochondrial function were assessed by invasive measurement of RV pressure-volume loops and by high-resolution respirometry at postnatal day 21 (P21), P90, and P365. In Results, at P21, hyperoxia-exposed rats demonstrated severe pulmonary hypertension and RV dysfunction, accompanied by depressed mitochondrial oxidative capacity. However, significant upregulation of mitochondrial biogenesis at P21 as well as improved afterload led to complete RV hemodynamic and mitochondrial recovery at P90. Mitochondrial DNA mutations were significantly higher by P90 and associated with significant late RV mitochondrial and hemodynamic dysfunction at P365. In conclusion, there appears to be a "honeymoon period" where cardiac hemodynamic and mitochondrial function normalizes following postnatal hyperoxia exposure, only to decline again with ongoing aging. This finding may have significant implications if a long-term pulmonary vascular screening program were to be developed for children or adults with a history of severe prematurity. Further investigation into the mechanisms of recovery are warranted.NEW & NOTEWORTHY Premature birth is associated with increased risk for cardiac dysfunction and failure throughout life. Here, we identify bimodal right ventricular dysfunction after postnatal hyperoxia exposure. Mitochondrial biogenesis serves as an early adaptive feature promoting recovery of cardiac hemodynamic and mitochondrial function. However, the accumulation of mitochondrial DNA mutations results in late mitochondrial and right ventricular dysfunction. This bimodal right ventricular dysfunction may have important implications for the development of screening programs in the preterm population.


Assuntos
Hiperóxia/complicações , Disfunção Ventricular Direita/fisiopatologia , Animais , DNA Mitocondrial/genética , Feminino , Coração/crescimento & desenvolvimento , Coração/fisiopatologia , Masculino , Mitocôndrias/metabolismo , Mutação , Biogênese de Organelas , Ratos , Ratos Sprague-Dawley , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/genética , Disfunção Ventricular Direita/metabolismo
13.
J Vis Exp ; (150)2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31475976

RESUMO

The incidence of clinical benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) is increasing due to the aging population, resulting in a significant economic and quality of life burden. Transgenic and other mouse models have been developed to recreate various aspects of this multifactorial disease; however, methods to accurately quantitate urinary dysfunction and the effectiveness of new therapeutic options are lacking. Here, we describe a method that can be used to measure bladder volume and detrusor wall thickness, urinary velocity, void volume and void duration, and urethral diameter. This would allow for the evaluation of disease progression and treatment efficacy over time. Mice were anesthetized with isoflurane, and the bladder was visualized by ultrasound. For non-contrast imaging, a 3D image was taken of the bladder to calculate volume and evaluate shape; the bladder wall thickness was measured from this image. For contrast-enhanced imaging, a catheter was placed through the dome of the bladder using a 27-gauge needle connected to a syringe by PE50 tubing. A bolus of 0.5 mL of contrast was infused into the bladder until a urination event occurred. Urethral diameter was determined at the point of the Doppler velocity sample window during the first voiding event. Velocity was measured for each subsequent event yielding a flow rate. In conclusion, high frequency ultrasound proved to be an effective method for assessing bladder and urethral measurements during urinary function in mice. This technique may be useful in the assessment of novel therapies for BPH/LUTS in an experimental setting.


Assuntos
Imageamento Tridimensional/métodos , Ultrassonografia/métodos , Fenômenos Fisiológicos do Sistema Urinário , Sistema Urinário/diagnóstico por imagem , Fatores Etários , Animais , Sintomas do Trato Urinário Inferior/diagnóstico por imagem , Sintomas do Trato Urinário Inferior/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hiperplasia Prostática/diagnóstico por imagem , Hiperplasia Prostática/fisiopatologia , Obstrução do Colo da Bexiga Urinária/diagnóstico por imagem , Obstrução do Colo da Bexiga Urinária/fisiopatologia , Micção/fisiologia
14.
EBioMedicine ; 46: 236-247, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31401194

RESUMO

BACKGROUND: Myocardial infarction (MI) is a life-threatening disease, often leading to heart failure. Defining therapeutic targets at an early time point is important to prevent heart failure. METHODS: MicroRNA screening was performed at early time points after MI using paired samples isolated from the infarcted and remote myocardium of pigs. We also examined the microRNA expression in plasma of MI patients and pigs. For mechanistic studies, AAV9-mediated microRNA knockdown and overexpression were administrated in mice undergoing MI. FINDINGS: MicroRNAs let-7a and let-7f were significantly downregulated in the infarct area within 24 h post-MI in pigs. We also observed a reduction of let-7a and let-7f in plasma of MI patients and pigs. Inhibition of let-7 exacerbated cardiomyocyte apoptosis, induced a cardiac hypertrophic phenotype, and resulted in worsened left ventricular ejection fraction. In contrast, ectopic let-7 overexpression significantly reduced those phenotypes and improved heart function. We then identified TGFBR3 as a target of let-7, and found that induction of Tgfbr3 in cardiomyocytes caused apoptosis, likely through p38 MAPK activation. Finally, we showed that the plasma TGFBR3 level was elevated after MI in plasma of MI patients and pigs. INTERPRETATION: Together, we conclude that the let-7-Tgfbr3-p38 MAPK signalling plays an important role in cardiomyocyte apoptosis after MI. Furthermore, microRNA let-7 and Tgfbr3 may serve as therapeutic targets and biomarkers for myocardial damage. FUND: Ministry of Science and Technology, National Health Research Institutes, Academia Sinica Program for Translational Innovation of Biopharmaceutical Development-Technology Supporting Platform Axis, Thematic Research Program and the Summit Research Program, Taiwan.


Assuntos
Apoptose/genética , Regulação da Expressão Gênica , MicroRNAs/genética , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Proteoglicanas/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais , Animais , Biomarcadores , Modelos Animais de Doenças , Ecocardiografia , Terapia Genética/métodos , Vetores Genéticos/genética , Humanos , Camundongos , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/terapia , Miócitos Cardíacos/metabolismo , Suínos , Fatores de Tempo , Transdução Genética , Remodelação Ventricular/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
Pharmacol Res Perspect ; 7(4): e00500, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31338199

RESUMO

Managing myocardial infarction (MI) to reduce cardiac cell death relies primarily on timely reperfusion of the affected coronary site, but reperfusion itself induces cell death through a toxic, ROS-mediated process. In this study, we determined whether the PrC-210 aminothiol ROS-scavenger could prevent ROS-induced damage in post-MI hearts. In a series of both in vitro and in vivo experiments, we show that: (a) in vitro, PrC-210 was the most potent and effective ROS-scavenger when functionally compared to eight of the most commonly studied antioxidants in the MI literature, (b) in vitro PrC-210 ROS-scavenging efficacy was both immediate (seconds) and long-lasting (hours), which would make it effective in both (1) real-time (seconds), as post-MI or cardiac surgery hearts are reperfused with PrC-210-containing blood, and (2) long-term (hours), as hearts are bathed with systemic PrC-210 after MI or surgery, (c) systemic PrC-210 caused a significant 36% reduction of mouse cardiac muscle death following a 45-minute cardiac IR insult; in a striking coincidence, the PrC-210 36% reduction in cardiac muscle death equals the 36% of the MI-induced cardiac cell death estimated 6 years ago by Ovize and colleagues to result from "reperfusion injury," (d) hearts in PrC-210-treated mice performed better than controls after heart attacks when functionally analyzed using echocardiography, and (e) the PrC-210 ROS-scavenging mechanism of action was corroborated by its ability to prevent >85% of the direct, H2O2-induced killing of neonate cardiomyocytes in cell culture. PrC-210 does not cause the nausea, emesis, nor hypotension that preclude clinical use of the WR-1065/amifostine aminothiol. PrC-210 is a highly effective ROS-scavenger that significantly reduces IR injury-associated cardiac cell death.


Assuntos
Diaminas/administração & dosagem , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Compostos de Sulfidrila/administração & dosagem , Animais , Morte Celular/efeitos dos fármacos , Células Cultivadas , Diaminas/farmacologia , Modelos Animais de Doenças , Peróxido de Hidrogênio/efeitos adversos , Masculino , Camundongos , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Compostos de Sulfidrila/farmacologia
16.
Stem Cells ; 37(7): 910-923, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31087611

RESUMO

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) exhibit a fetal phenotype that limits in vitro and therapeutic applications. Strategies to promote cardiomyocyte maturation have focused interventions on differentiated hPSC-CMs, but this study tests priming of early cardiac progenitor cells (CPCs) with polyinosinic-polycytidylic acid (pIC) to accelerate cardiomyocyte maturation. CPCs were differentiated from hPSCs using a monolayer differentiation protocol with defined small molecule Wnt temporal modulation, and pIC was added during the formation of early CPCs. pIC priming did not alter the expression of cell surface markers for CPCs (>80% KDR+/PDGFRα+), expression of common cardiac transcription factors, or final purity of differentiated hPSC-CMs (∼90%). However, CPC differentiation in basal medium revealed that pIC priming resulted in hPSC-CMs with enhanced maturity manifested by increased cell size, greater contractility, faster electrical upstrokes, increased oxidative metabolism, and more mature sarcomeric structure and composition. To investigate the mechanisms of CPC priming, RNAseq revealed that cardiac progenitor-stage pIC modulated early Notch signaling and cardiomyogenic transcriptional programs. Chromatin immunoprecipitation of CPCs showed that pIC treatment increased deposition of the H3K9ac activating epigenetic mark at core promoters of cardiac myofilament genes and the Notch ligand, JAG1. Inhibition of Notch signaling blocked the effects of pIC on differentiation and cardiomyocyte maturation. Furthermore, primed CPCs showed more robust formation of hPSC-CMs grafts when transplanted to the NSGW mouse kidney capsule. Overall, epigenetic modulation of CPCs with pIC accelerates cardiomyocyte maturation enabling basic research applications and potential therapeutic uses. Stem Cells 2019;37:910-923.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Epigênese Genética , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Poli I-C/farmacologia , Receptores Notch/genética , Animais , Tamanho Celular , Histonas/genética , Histonas/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/transplante , Proteína Jagged-1/genética , Proteína Jagged-1/metabolismo , Rim , Camundongos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Fosforilação Oxidativa , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores Notch/metabolismo , Sarcômeros/metabolismo , Análise de Sequência de RNA , Transdução de Sinais , Transplante de Células-Tronco/métodos , Transplante Heterotópico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
17.
Am J Physiol Heart Circ Physiol ; 316(5): H1005-H1013, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30822119

RESUMO

Right ventricular failure (RVF) is a common cause of death in patients suffering from pulmonary arterial hypertension (PAH). The current treatment for PAH only moderately improves symptoms, and RVF ultimately occurs. Therefore, it is necessary to develop new treatment strategies to protect against right ventricle (RV) maladaptation despite PAH progression. In this study, we hypothesize that local mesenchymal stem cell (MSC) delivery via a novel bioscaffold can improve RV function despite persistent PAH. To test our hypothesis, we induced PAH in adult rats with SU5416 and chronic hypoxia exposure; treated with rat MSCs delivered by intravenous injection, intramyocardial injection, or epicardial placement of a bioscaffold; and then examined treatment effectiveness by in vivo pressure-volume measurement, echocardiography, histology, and immunohistochemistry. Our results showed that compared with other treatment groups, only the MSC-seeded bioscaffold group resulted in RV functional improvement, including restored stroke volume, cardiac output, and improved stroke work. Diastolic function indicated by end-diastolic pressure-volume relationship was improved by the local MSC treatments or bioscaffold alone. Cardiomyocyte hypertrophy and RV fibrosis were both reduced, and von Willebrand factor expression was restored by the MSC-seeded bioscaffold treatment. Overall, our study suggests a potential new regenerative therapy to rescue the pressure-overload failing RV with persistent pulmonary vascular disease, which may improve quality of life and/or survival of PAH patients. NEW & NOTEWORTHY We explored the effects of mesenchymal stem cell-seeded bioscaffold on right ventricles (RVs) of rats with established pulmonary arterial hypertension (PAH). Some beneficial effects were observed despite persistent PAH, suggesting that this may be a new therapy for RV to improve quality of life and/or survival of PAH patients.


Assuntos
Pressão Arterial , Hipertrofia Ventricular Direita/cirurgia , Transplante de Células-Tronco Mesenquimais/métodos , Hipertensão Arterial Pulmonar/cirurgia , Artéria Pulmonar/fisiopatologia , Tecidos Suporte , Disfunção Ventricular Direita/cirurgia , Função Ventricular Direita , Animais , Células Cultivadas , Modelos Animais de Doenças , Fibrose , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/metabolismo , Hipertrofia Ventricular Direita/fisiopatologia , Hipóxia/complicações , Indóis , Masculino , Contração Miocárdica , Miocárdio/metabolismo , Miocárdio/patologia , Hipertensão Arterial Pulmonar/etiologia , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/fisiopatologia , Pirróis , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Regeneração , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/metabolismo , Disfunção Ventricular Direita/fisiopatologia , Remodelação Ventricular , Fator de von Willebrand/metabolismo
18.
Am J Physiol Heart Circ Physiol ; 316(5): H1167-H1177, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30767670

RESUMO

Left heart failure (LHF) is the most common cause of pulmonary hypertension, which confers an increase in morbidity and mortality in this context. Pulmonary vascular resistance has prognostic value in LHF, but otherwise the mechanical consequences of LHF for the pulmonary vasculature and right ventricle (RV) remain unknown. We sought to investigate mechanical mechanisms of pulmonary vascular and RV dysfunction in a rodent model of LHF to address the knowledge gaps in understanding disease pathophysiology. LHF was created using a left anterior descending artery ligation to cause myocardial infarction (MI) in mice. Sham animals underwent thoracotomy alone. Echocardiography demonstrated increased left ventricle (LV) volumes and decreased ejection fraction at 4 wk post-MI that did not normalize by 12 wk post-MI. Elevation of LV diastolic pressure and RV systolic pressure at 12 wk post-MI demonstrated pulmonary hypertension (PH) due to LHF. There was increased pulmonary arterial elastance and pulmonary vascular resistance associated with perivascular fibrosis without other remodeling. There was also RV contractile dysfunction with a 35% decrease in RV end-systolic elastance and 66% decrease in ventricular-vascular coupling. In this model of PH due to LHF with reduced ejection fraction, pulmonary fibrosis contributes to increased RV afterload, and loss of RV contractility contributes to RV dysfunction. These are key pathologic features of human PH secondary to LHF. In the future, novel therapeutic strategies aimed at preventing pulmonary vascular mechanical changes and RV dysfunction in the context of LHF can be tested using this model. NEW & NOTEWORTHY In this study, we investigate the mechanical consequences of left heart failure with reduced ejection fraction for the pulmonary vasculature and right ventricle. Using comprehensive functional analyses of the cardiopulmonary system in vivo and ex vivo, we demonstrate that pulmonary fibrosis contributes to increased RV afterload and loss of RV contractility contributes to RV dysfunction. Thus this model recapitulates key pathologic features of human pulmonary hypertension-left heart failure and offers a robust platform for future investigations.


Assuntos
Insuficiência Cardíaca/fisiopatologia , Infarto do Miocárdio/fisiopatologia , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/fisiopatologia , Circulação Pulmonar , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Direita/fisiopatologia , Função Ventricular Esquerda , Função Ventricular Direita , Animais , Modelos Animais de Doenças , Fibrose , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/etiologia , Masculino , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/etiologia , Hipertensão Arterial Pulmonar/diagnóstico por imagem , Hipertensão Arterial Pulmonar/etiologia , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/patologia , Volume Sistólico , Remodelação Vascular , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Direita/diagnóstico por imagem , Disfunção Ventricular Direita/etiologia , Pressão Ventricular
19.
Circulation ; 139(5): 647-659, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30586712

RESUMO

BACKGROUND: The impact of gut microbiota on the regulation of host physiology has recently garnered considerable attention, particularly in key areas such as the immune system and metabolism. These areas are also crucial for the pathophysiology of and repair after myocardial infarction (MI). However, the role of the gut microbiota in the context of MI remains to be fully elucidated. METHODS: To investigate the effects of gut microbiota on cardiac repair after MI, C57BL/6J mice were treated with antibiotics 7 days before MI to deplete mouse gut microbiota. Flow cytometry was applied to examine the changes in immune cell composition in the heart. 16S rDNA sequencing was conducted as a readout for changes in gut microbial composition. Short-chain fatty acid (SCFA) species altered after antibiotic treatment were identified by high-performance liquid chromatography. Fecal reconstitution, transplantation of monocytes, or dietary SCFA or Lactobacillus probiotic supplementation was conducted to evaluate the cardioprotective effects of microbiota on the mice after MI. RESULTS: Antibiotic-treated mice displayed drastic, dose-dependent mortality after MI. We observed an association between the gut microbiota depletion and significant reductions in the proportion of myeloid cells and SCFAs, more specifically acetate, butyrate, and propionate. Infiltration of CX3CR1+ monocytes to the peri-infarct zone after MI was also reduced, suggesting impairment of repair after MI. Accordingly, the physiological status and survival of mice were significantly improved after fecal reconstitution, transplantation of monocytes, or dietary SCFA supplementation. MI was associated with a reorganization of the gut microbial community such as a reduction in Lactobacillus. Supplementing antibiotic-treated mice with a Lactobacillus probiotic before MI restored myeloid cell proportions, yielded cardioprotective effects, and shifted the balance of SCFAs toward propionate. CONCLUSIONS: Gut microbiota-derived SCFAs play an important role in maintaining host immune composition and repair capacity after MI. This suggests that manipulation of these elements may provide opportunities to modulate pathological outcome after MI and indeed human health and disease as a whole.


Assuntos
Antibacterianos/toxicidade , Bactérias/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Monócitos/imunologia , Infarto do Miocárdio/microbiologia , Miocárdio/imunologia , Animais , Bactérias/imunologia , Bactérias/metabolismo , Modelos Animais de Doenças , Disbiose , Ácidos Graxos/administração & dosagem , Ácidos Graxos/metabolismo , Transplante de Microbiota Fecal , Feminino , Interações Hospedeiro-Patógeno , Lactobacillus/imunologia , Lactobacillus/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Monócitos/metabolismo , Monócitos/transplante , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Probióticos/administração & dosagem , Células RAW 264.7
20.
Adv Exp Med Biol ; 1098: 45-58, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30238365

RESUMO

Cardiovascular disease has been the leading cause of death worldwide for the last 15 years, accounting for 15 million deaths per year. While interventions are saving more lives, more than 20% of survivors will end up in heart failure. Cell-based and other types of therapy for advanced heart and vascular disease may offer new hope for those afflicted. Although a variety of cell types are under investigation, common issues include cell survival, retention, engraftment, and proliferation. Cardiac extracellular matrix (C-ECM) has compelling features that offer advantages to not only aid cell survival, retention, engraftment, and proliferation but likely has independent therapeutic (paracrine) and mechanical effects. Animal studies and clinical trials are underway to characterize the role of C-ECM and demonstrate efficacy for acute and chronic heart disease. This chapter reviews animal models used to enhance our knowledge of C-ECMs in heart disease and its use in the treatment of heart disease.


Assuntos
Matriz Extracelular/fisiologia , Coração/fisiologia , Modelos Animais , Miocárdio/metabolismo , Animais , Animais Geneticamente Modificados , Células Cultivadas , Modelos Animais de Doenças , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Projetos de Pesquisa
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