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Theranostics ; 11(16): 7879-7895, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335970


Rationale: Previous studies have shown that human embryonic stem cell-derived cardiomyocytes improved myocardial recovery when administered to infarcted pig and non-human primate hearts. However, the engraftment of intramyocardially delivered cells is poor and the effectiveness of clinically relevant doses of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in large animal models of myocardial injury remains unknown. Here, we determined whether thymosin ß4 (Tb4) could improve the engraftment and reparative potency of transplanted hiPSC-CMs in a porcine model of myocardial infarction (MI). Methods: Tb4 was delivered from injected gelatin microspheres, which extended the duration of Tb4 administration for up to two weeks in vitro. After MI induction, pigs were randomly distributed into 4 treatment groups: the MI Group was injected with basal medium; the Tb4 Group received gelatin microspheres carrying Tb4; the CM Group was treated with 1.2 × 108 hiPSC-CMs; and the Tb4+CM Group received both the Tb4 microspheres and hiPSC-CMs. Myocardial recovery was assessed by cardiac magnetic resonance imaging (MRI), arrhythmogenesis was monitored with implanted loop recorders, and tumorigenesis was evaluated via whole-body MRI. Results: In vitro, 600 ng/mL of Tb4 protected cultured hiPSC-CMs from hypoxic damage by upregulating AKT activity and BcL-XL and promoted hiPSC-CM and hiPSC-EC proliferation. In infarcted pig hearts, hiPSC-CM transplantation alone had a minimal effect on myocardial recovery, but co-treatment with Tb4 significantly enhanced hiPSC-CM engraftment, induced vasculogenesis and the proliferation of cardiomyocytes and endothelial cells, improved left ventricular systolic function, and reduced infarct size. hiPSC-CM implantation did not increase incidence of ventricular arrhythmia and did not induce tumorigenesis in the immunosuppressed pigs. Conclusions: Co-treatment with Tb4-microspheres and hiPSC-CMs was safe and enhanced the reparative potency of hiPSC-CMs for myocardial repair in a large-animal model of MI.

Infarto do Miocárdio/terapia , Miócitos Cardíacos/metabolismo , Timosina/farmacologia , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , China , Modelos Animais de Doenças , Células Endoteliais/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Infarto do Miocárdio/metabolismo , Miocárdio/patologia , Regeneração , Transplante de Células-Tronco/métodos , Suínos , Timosina/metabolismo , Timosina/fisiologia
J Mol Cell Cardiol ; 144: 15-23, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32387242


AIMS: Recently, we demonstrated that the hearts of neonatal pigs (2-day old) have regenerative capacity, likely driven by cardiac myocyte division, but this potential is lost immediately after postnatal day 3. However, it is unknown if corticosteroid, a broad anti-inflammatory agent, will abrogate the regenerative capacity in the hearts of neonatal pigs. The aim of the current study is to evaluate the effect Dexamethasone (Dex), a broad anti-inflammatory agent, on heart regeneration, structure, and function of the neonatal pigs' post-myocardial infarction (MI). METHODS AND RESULTS: Dex (0.2 mg/kg/day) was injected intramuscularly into the neonatal pig (age: 2 days postnatal) during the first week post-MI. Myocardial scar and left ventricular function were determined by cardiac magnetic resonance (CMR) imaging. Bromodeoxyuridine (BrdU) pulse-chase labeling, histology, immunohistochemistry, and flow cytometry were performed to determine inflammatory cell infiltration, CM cytokinesis, and myocardial fibrosis. Dex injection during the first-week suppressed acute inflammation post-MI in the pig hearts. It inhibited BrdU incorporation to pig CMs and CM cytokinesis via inhibiting aurora-B protein expression which was associated with mature scar formation and thinned walls at the infarct site. CMR imaging showed Dex caused left ventricular aneurysm and poor ejection fraction. CONCLUSIONS: Dex inhibited CM cytokinesis and functional recovery and caused ventricular aneurysm in the hearts of 2-day old pigs post-MI.

J Am Chem Soc ; 142(7): 3430-3439, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32040300


Pancreatic ß cells are responsible for insulin secretion and are important for glucose regulation in a healthy body and diabetic disease patient without prelabeling of islets. While the conventional biomarkers for diabetes have been glucose and insulin concentrations in the blood, the direct determination of the pancreatic ß cell mass would provide critical information for the disease status and progression. By combining fluorination and diversity-oriented fluorescence library strategy, we have developed a multimodal pancreatic ß cell probe PiF for both fluorescence and for PET (positron emission tomography). By simple tail vein injection, PiF stains pancreatic ß cells specifically and allows intraoperative fluorescent imaging of pancreatic islets. PiF-injected pancreatic tissue even facilitated an antibody-free islet analysis within 2 h, dramatically accelerating the day-long histological procedure without any fixing and dehydration step. Not only islets in the pancreas but also the low background of PiF in the liver allowed us to monitor the intraportal transplanted islets, which is the first in vivo visualization of transplanted human islets without a prelabeling of the islets. Finally, we could replace the built-in fluorine atom in PiF with radioactive 18F and successfully demonstrate in situ PET imaging for pancreatic islets.

Corantes Fluorescentes/química , Células Secretoras de Insulina/citologia , Xantenos/química , Animais , Diabetes Mellitus Experimental/patologia , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacocinética , Corantes Fluorescentes/toxicidade , Humanos , Células Secretoras de Insulina/transplante , Transplante das Ilhotas Pancreáticas , Fígado/citologia , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Tomografia por Emissão de Pósitrons , Ratos , Xantenos/síntese química , Xantenos/farmacocinética , Xantenos/toxicidade
Diabetes Obes Metab ; 21(2): 357-365, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30225964


AIM: To investigate the effects of the sodium-glucose co-transporter-2 inhibitor empagliflozin on myocardial ketone body utilization in diabetic, obese rats with spontaneously hypertensive heart failure (SHHF), after 6 months of treatment. MATERIALS AND METHODS: Myocardial ketone body utilization was measured in vivo real time using a novel ketone probe (hyperpolarized [3-13 C]acetoacetate) and magnetic resonance spectroscopy (MRS). Myocardial glucose utilization and cardiac function were also determined in vivo using hyperpolarized [1-13 C]pyruvate MRS and magnetic resonance imaging (MRI), respectively. Myocardial fatty acid uptake and liver ketogenesis were assessed via protein expression. RESULTS: At baseline, myocardial ketone and glucose utilization were both higher in SHHF compared with control rats. Six months of empagliflozin treatment in SHHF rats was associated with less obesity, lower blood pressure, reduced blood glucose and insulin levels, and increased fasting blood ß-hydroxybutyrate levels, as expected. Contrary to the hypothesis, myocardial ketone body utilization was lower in empagliflozin-treated SHHF rats, while glucose utilization and cardiac function were unaltered and hepatic congestion was reduced, compared with vehicle-treated SHHF rats. CONCLUSIONS: In diabetic hypertensive heart disease, empagliflozin reduces afterload without altering myocardial function and glucose utilization in the face of falling blood glucose levels, but does not enhance myocardial ketone utilization despite increased circulating levels.

Compostos Benzidrílicos/uso terapêutico , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Diabetes Mellitus Experimental , Angiopatias Diabéticas/diagnóstico , Glucose/metabolismo , Glucosídeos/uso terapêutico , Cetonas/metabolismo , Miocárdio/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13/métodos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/diagnóstico , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/patologia , Angiopatias Diabéticas/prevenção & controle , Coração/diagnóstico por imagem , Masculino , Miocárdio/química , Obesidade/complicações , Obesidade/diagnóstico , Obesidade/metabolismo , Obesidade/patologia , Ratos , Ratos Endogâmicos SHR , Ratos Sprague-Dawley , Ganho de Peso/efeitos dos fármacos
Diabetes Obes Metab ; 21(4): 949-960, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30536560


AIM: To investigate the effects of long-term low-carbohydrate low-protein ketogenic diet (KD) on cardiac metabolism and diabetic cardiomyopathy status in lean diabetic Goto-Kakizaki (GK) rats. MATERIALS AND METHODS: Diabetic GK rats were fed with KD for 62 weeks. Cardiac function and metabolism were assessed using magnetic resonance imaging and 13 C magnetic resonance spectroscopy (13 C-MRS), at rest and under dobutamine stress. 13 C-MRS was performed following injection of hyperpolarized [3-13 C]acetoacetate, [1-13 C]butyrate or [1-13 C]pyruvate to assess ketone body, short-chain fatty acid or glucose utilization, respectively. Protein expression and cardiomyocyte structure were determined via Western blotting and histology, respectively. RESULTS: KD lowered blood glucose, triglyceride and insulin levels while increasing blood ketone body levels. In KD-fed diabetic rats, myocardial ketone body and glucose oxidation were lower than in chow-fed diabetic rats, while myocardial glycolysis and short-chain fatty acid oxidation were unaltered. Dobutamine stress revealed an increased cardiac preload and reduced cardiac compliance in KD-fed diabetic rats. Dobutamine-induced stimulation of myocardial glycolysis was more enhanced in KD-fed diabetic rats than in chow-fed diabetic rats, which was potentially facilitated via an upregulation in basal expression of proteins involved in glucose transport and glycolysis in the hearts of KD-fed rats. The metabolic profile induced by KD was accompanied by cardiac hypertrophy, a trend for increased myocardial lipid and collagen content, and an increased marker of oxidative stress. CONCLUSION: KD seems to exacerbate diabetic cardiomyopathy in GK rats, which may be associated with maladaptive cardiac metabolic modulation and lipotoxicity.

Diabetes Mellitus/metabolismo , Dieta Cetogênica , Dieta com Restrição de Proteínas , Glucose/metabolismo , Corpos Cetônicos/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Acetoacetatos , Animais , Glicemia/metabolismo , Butiratos , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Cardiotônicos , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Dieta com Restrição de Carboidratos , Dobutamina , Ácidos Graxos Voláteis/metabolismo , Glicólise , Insulina/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/patologia , Ácido Pirúvico , Ratos , Triglicerídeos/metabolismo
Circulation ; 138(24): 2798-2808, 2018 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-30030417


BACKGROUND: The adult mammalian heart has limited ability to repair itself after injury. Zebrafish, newts, and neonatal mice can regenerate cardiac tissue, largely by cardiac myocyte (CM) proliferation. It is unknown whether hearts of young large mammals can regenerate. METHODS: We examined the regenerative capacity of the pig heart in neonatal animals (ages 2, 3, or 14 days postnatal) after myocardial infarction or sham procedure. Myocardial scar and left ventricular function were determined by cardiac magnetic resonance imaging and echocardiography. Bromodeoxyuridine pulse-chase labeling, histology, immunohistochemistry, and Western blotting were performed to study cell proliferation, sarcomere dynamics, and cytokinesis and to quantify myocardial fibrosis. RNA-sequencing was also performed. RESULTS: After myocardial infarction, there was early and sustained recovery of cardiac function and wall thickness in the absence of fibrosis in 2-day-old pigs. In contrast, older animals developed full-thickness myocardial scarring, thinned walls, and did not recover function. Genome-wide analyses of the infarct zone revealed a strong transcriptional signature of fibrosis in 14-day-old animals that was absent in 2-day-old pigs, which instead had enrichment for cytokinesis genes. In regenerating hearts of the younger animals, up to 10% of CMs in the border zone of the myocardial infarction showed evidence of DNA replication that was associated with markers of myocyte division and sarcomere disassembly. CONCLUSIONS: Hearts of large mammals have regenerative capacity, likely driven by cardiac myocyte division, but this potential is lost immediately after birth.

Coração/fisiologia , Infarto do Miocárdio/patologia , Animais , Animais Recém-Nascidos , Citocinese/genética , Ecocardiografia , Fibrose , Imagem Cinética por Ressonância Magnética , Infarto do Miocárdio/diagnóstico por imagem , Miocárdio/patologia , Miócitos Cardíacos/fisiologia , Regeneração , Suínos , Troponina I/análise , Função Ventricular Esquerda