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1.
J Surg Res ; 276: 354-361, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35429684

RESUMEN

INTRODUCTION: Gastrointestinal anastomoses are performed millions of times per year worldwide. The major complication they share is anastomotic leak. We describe the development and initial safety/efficacy of a novel luminal stent which aims to address this clinical issue. MATERIALS AND METHODS: The stent was created out of two materials, a polyvinyl alcohol core and outer layer of acellular porcine small intestine submucosa. Ten healthy pigs underwent laparotomy, a portion of the colon was transected, and the stent was placed within the colonic lumen at the site of resection. Pigs were sacrificed at the end of postoperative week 2, and postoperative week 4. A portion of the descending colon was resected, and tissue samples from the anastomosis, intentional defect scar, and normal bowel overlying the stent were sent for histopathologic examination. RESULTS: All ten animals survived the study. None developed any clinical signs of obstruction, infection, leakage, fistula, wound complications, or bleeding. No evidence of colonic leak or luminal stenosis/stricture was noted. CONCLUSIONS: The results of this study show that a polyvinyl alcohol/acellular porcine small intestine submucosa stent sewn underneath a colonic anastomosis with a 2 cm intentional defect will result in no anastomotic complications. There were also no complications from placing this stent in any pigs. Additional studies with a control group should be conducted to see if this same stent can be built in different diameters, lengths, and configurations to prevent leaks in other organs. These encouraging results will hopefully lead to decreased leaks and the need for temporary ostomies in humans.


Asunto(s)
Fuga Anastomótica , Alcohol Polivinílico , Anastomosis Quirúrgica/efectos adversos , Anastomosis Quirúrgica/métodos , Fuga Anastomótica/etiología , Fuga Anastomótica/patología , Fuga Anastomótica/prevención & control , Animales , Colon/patología , Colon/cirugía , Intestino Delgado/cirugía , Stents/efectos adversos , Porcinos
2.
Basic Res Cardiol ; 114(2): 9, 2019 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-30656501

RESUMEN

Enthusiasm for cell therapy for myocardial injury has waned due to equivocal benefits in clinical trials. In an attempt to improve efficacy, we investigated repeated cell therapy and adjunct renal denervation (RDN) as strategies for augmenting cardioprotection with cardiosphere-derived cells (CDCs). We hypothesized that combining CDC post-conditioning with repeated CDC doses or delayed RDN therapy would result in superior function and remodeling. Wistar-Kyoto (WKY) rats or spontaneously hypertensive rats (SHR) were subjected to 45 min of coronary artery ligation followed by reperfusion for 12-14 weeks. In the first study arm, SHR were treated with CDCs (0.5 × 106 i.c.) or PBS 20 min following reperfusion, or additionally treated with CDCs (1.0 × 106 i.v.) at 2, 4, and 8 weeks. In the second arm, at 4 weeks following myocardial infarction (MI), SHR received CDCs (0.5 × 106 i.c.) or CDCs + RDN. In the third arm, WKY rats were treated with i.c. CDCs administered 20 min following reperfusion and RDN or a sham at 4 weeks. Early i.c. + multiple i.v. dosing, but not single i.c. dosing, of CDCs improved long-term left ventricular (LV) function, but not remodeling. Delayed CDC + RDN therapy was not superior to single-dose delayed CDC therapy. Early CDC + delayed RDN therapy improved LV ejection fraction and remodeling compared to both CDCs alone and RDN alone. Given that both RDN and CDCs are currently in the clinic, our findings motivate further translation targeting a heart failure indication with combined approaches.


Asunto(s)
Desnervación Autonómica/métodos , Daño por Reperfusión Miocárdica , Trasplante de Células Madre/métodos , Animales , Insuficiencia Cardíaca , Riñón/inervación , Riñón/cirugía , Masculino , Infarto del Miocardio , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Remodelación Ventricular/fisiología
3.
Circ Res ; 119(3): 470-80, 2016 07 22.
Artículo en Inglés | MEDLINE | ID: mdl-27296507

RESUMEN

RATIONALE: Catheter-based renal denervation (RDN) is currently under development for the treatment of resistant hypertension and is thought to reduce blood pressure via interruption of sympathetic pathways that modulate cardiovascular function. The sympathetic nervous system also plays a critical role in the pathogenesis of acute myocardial infarction and heart failure. OBJECTIVE: We examined whether treatment with radiofrequency (RF)-RDN would protect the heart against subsequent myocardial ischemia/reperfusion injury via direct effects on the myocardium. METHODS AND RESULTS: Spontaneously hypertensive rats received either bilateral RF-RDN or sham-RDN. At 4 weeks after RF-RDN (n=14) or sham-RDN (n=14) treatment, spontaneously hypertensive rats were subjected to 30 minutes of transient coronary artery occlusion and 24 hours -7 days reperfusion. Four weeks after RF-RDN, myocardial oxidative stress was markedly attenuated, and transcription and translation of antioxidants, superoxide dismutase 1 and glutathione peroxidase-1, were significantly upregulated compared with sham-RDN spontaneously hypertensive rats. RF-RDN also inhibited myocardial G protein-coupled receptor kinase 2 pathological signaling and enhanced myocardial endothelial nitric oxide synthase function and nitric oxide signaling. RF-RDN therapy resulted in a significant reduction in myocardial infarct size per area at risk compared with sham-RDN (26.8 versus 43.9%; P<0.01) at 24 hours postreperfusion and significantly improved left ventricular function at 7 days after myocardial ischemia/reperfusion. CONCLUSIONS: RF-RDN reduced oxidative stress, inhibited G protein-coupled receptor kinase 2 signaling, increased nitric oxide bioavailability, and ameliorated myocardial reperfusion injury in the setting of severe hypertension. These findings provide new insights into the remote cardioprotective effects of RF-RDN acting directly on cardiac myocytes to attenuate cell death and protect against ischemic injury.


Asunto(s)
Ablación por Catéter/métodos , Quinasa 2 del Receptor Acoplado a Proteína-G/metabolismo , Riñón/metabolismo , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/prevención & control , Óxido Nítrico/biosíntesis , Animales , Desnervación/métodos , Quinasa 2 del Receptor Acoplado a Proteína-G/antagonistas & inhibidores , Riñón/inervación , Riñón/cirugía , Masculino , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Estrés Oxidativo/fisiología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Transducción de Señal/fisiología
4.
medRxiv ; 2024 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-38826318

RESUMEN

Background: Angiotensin (Ang)-II impairs the function of the antihypertensive enzyme ACE2 by promoting its internalization, ubiquitination and degradation thus contributing to hypertension. However, few ACE2 ubiquitination partners have been identified and their role in hypertension remains unknown. Methods: Proteomics and bioinformatic analysis were used to identify ACE2 ubiquitination partners in the brain, heart, and kidney from Ang-II-infused C57BL6/J mice from both sexes and validated the interaction between UBR1 and ACE2 in cells. Central and peripheral UBR1 knockdown was then performed in male mice to investigate its role in the maintenance of hypertension. Results: Proteomics analysis from hypothalamus identified UBR1 as a potential E3 ligase promoting ACE2 ubiquitination. Enhanced UBR1 expression, associated with ACE2 reduction, was confirmed in various tissues from hypertensive male mice and human samples. Treatment of endothelial and smooth muscle cells with testosterone, but not 17ß-estradiol, confirmed a sex-specific regulation of UBR1. In vivo silencing of UBR1 using chronic administration of small interference RNA resulted in the restoration of ACE2 levels in hypertensive males. A transient decrease in blood pressure following intracerebroventricular, but not systemic, infusion was also observed. Interestingly, UBR1 knockdown increased the brain activation of Nedd4-2, an E3 ligase promoting ACE2 ubiquitination and reduced expression of SGK1, the kinase inactivating Nedd4-2. Conclusions: These data demonstrate that UBR1 is a novel ubiquitin ligase targeting ACE2 in hypertension. UBR1 and Nedd4-2 E3 ligases appear to work synergistically to ubiquitinate ACE2. Targeting of these ubiquitin ligases may represent a novel strategy to restore ACE2 compensatory activity in hypertension.

5.
JCI Insight ; 8(4)2023 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-36602878

RESUMEN

Although murine models of coronary atherosclerotic disease have been used extensively to determine mechanisms, limited new therapeutic options have emerged. Pigs with familial hypercholesterolemia (FH pigs) develop complex coronary atheromas that are almost identical to human lesions. We reported previously that insulin-like growth factor 1 (IGF-1) reduced aortic atherosclerosis and promoted features of stable plaque in a murine model. We administered human recombinant IGF-1 or saline (control) in atherosclerotic FH pigs for 6 months. IGF-1 decreased relative coronary atheroma in vivo (intravascular ultrasound) and reduced lesion cross-sectional area (postmortem histology). IGF-1 increased plaque's fibrous cap thickness, and reduced necrotic core, macrophage content, and cell apoptosis, consistent with promotion of a stable plaque phenotype. IGF-1 reduced circulating triglycerides, markers of systemic oxidative stress, and CXCL12 chemokine levels. We used spatial transcriptomics (ST) to identify global transcriptome changes in advanced plaque compartments and to obtain mechanistic insights into IGF-1 effects. ST analysis showed that IGF-1 suppressed FOS/FOSB factors and gene expression of MMP9 and CXCL14 in plaque macrophages, suggesting possible involvement of these molecules in IGF-1's effect on atherosclerosis. Thus, IGF-1 reduced coronary plaque burden and promoted features of stable plaque in a pig model, providing support for consideration of clinical trials.


Asunto(s)
Aterosclerosis , Enfermedad de la Arteria Coronaria , Hiperlipoproteinemia Tipo II , Placa Aterosclerótica , Ratones , Humanos , Animales , Porcinos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Aterosclerosis/patología , Placa Aterosclerótica/patología
6.
JACC Basic Transl Sci ; 6(2): 154-170, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33665515

RESUMEN

A lack of preclinical large animal models of heart failure with preserved ejection fraction (HFpEF) that recapitulate this comorbid-laden syndrome has led to the inability to tease out mechanistic insights and to test novel therapeutic strategies. This study developed a large animal model that integrated multiple comorbid determinants of HFpEF in a miniswine breed that exhibited sensitivity to obesity, metabolic syndrome, and vascular disease with overt clinical signs of heart failure. The combination of a Western diet and 11-deoxycorticosterone acetate salt-induced hypertension in the Göttingen miniswine led to the development of a novel large animal model of HFpEF that exhibited multiorgan involvement and a full spectrum of comorbidities associated with human HFpEF.

7.
JACC Basic Transl Sci ; 5(7): 699-714, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32760857

RESUMEN

With the complexities that surround myocardial ischemia/reperfusion (MI/R) injury, therapies adjunctive to reperfusion that elicit beneficial pleiotropic effects and do not overlap with standard of care are necessary. This study found that the mitochondrial-derived peptide S14G-humanin (HNG) (2 mg/kg), an analogue of humanin, reduced infarct size in a large animal model of MI/R. However, when ischemic time was increased, the infarct-sparing effects were abolished with the same dose of HNG. Thus, although the 60-min MI/R study showed that HNG cardioprotection translates beyond small animal models, further studies are needed to optimize HNG therapy for longer, more patient-relevant periods of cardiac ischemia.

8.
J Am Heart Assoc ; 7(5)2018 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-29502102

RESUMEN

BACKGROUND: There is a paucity of data about the mechanisms by which sacubitril/valsartan (also known as LCZ696) improves outcomes in patients with heart failure. Specifically, the effects of sacubitril/valsartan on vascular function and NO bioavailability have not been investigated. We hypothesized that sacubitril/valsartan therapy increases circulating NO levels and improves vascular function in the setting of heart failure. METHODS AND RESULTS: Male spontaneously hypertensive rats underwent myocardial ischemia/reperfusion surgery to induce heart failure and were followed for up to 12 weeks with serial echocardiography. Rats received sacubitril/valsartan (68 mg/kg), valsartan (31 mg/kg), or vehicle starting at 4 weeks after reperfusion. At 8 or 12 weeks of reperfusion, animals were euthanized and tissues were collected for ex vivo analyses of NO bioavailability, aortic vascular reactivity, myocardial and vascular histology, and cardiac molecular assays. Left ventricular structure and function were improved by both valsartan and sacubitril/valsartan compared with vehicle. Sacubitril/valsartan resulted in superior cardiovascular benefits, as evidenced by sustained improvements in left ventricular ejection fraction and end-diastolic pressure. Ex vivo vascular function, as measured by aortic vasorelaxation responses to acetylcholine and sodium nitroprusside, was significantly improved by valsartan and sacubitril/valsartan, with more sustained improvements afforded by sacubitril/valsartan. Furthermore, myocardial NO bioavailability was significantly enhanced in animals receiving sacubitril/valsartan therapy. CONCLUSIONS: Sacubitril/valsartan offers superior cardiovascular protection in heart failure and improves vascular function to a greater extent than valsartan alone. Sacubitril/valsartan-mediated improvements in cardiac and vascular function are likely related to increases in NO bioavailability and explain, in part, the benefits beyond angiotensin receptor blockade.


Asunto(s)
Aminobutiratos/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Aorta Torácica/efectos de los fármacos , Insuficiencia Cardíaca/tratamiento farmacológico , Miocardio/metabolismo , Neprilisina/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Inhibidores de Proteasas/farmacología , Volumen Sistólico/efectos de los fármacos , Tetrazoles/farmacología , Función Ventricular Izquierda/efectos de los fármacos , Animales , Aorta Torácica/metabolismo , Aorta Torácica/fisiopatología , Compuestos de Bifenilo , Modelos Animales de Enfermedad , Combinación de Medicamentos , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Hipertensión/complicaciones , Hipertensión/metabolismo , Hipertensión/fisiopatología , Masculino , Miocardio/patología , Péptidos Natriuréticos/sangre , Neprilisina/metabolismo , Ratas Endogámicas SHR , Valsartán
9.
J Am Coll Cardiol ; 70(17): 2139-2153, 2017 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-29050562

RESUMEN

BACKGROUND: Sustained sympathetic activation contributes to the progression of myocardial cell injury, cardiac fibrosis, and left ventricular (LV) dysfunction in heart failure (HF). OBJECTIVES: This study investigated the effects of radiofrequency renal nerve denervation (RF-RDN) on the pathobiology of HF and the interaction between the renal sympathetic nerves and natriuretic peptide (NP) metabolism. METHODS: Spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) were subjected to 45 min of coronary artery ligation and reperfusion for 12 weeks. At 4 weeks post-reperfusion, SHR and WKY underwent either bilateral RF-RDN or sham-RDN. RESULTS: Following RF-RDN in both strains, LV ejection fraction remained significantly above those levels in respective sham-RDN rats, and at the end of the 12-week study, rats in both strains had significantly reduced LV fibrosis and improved vascular function. RF-RDN therapy significantly improved vascular reactivity to endothelium-dependent and -independent vasodilators as well as vascular compliance in the setting of severe HF. Improvements in LV function were accompanied by significant elevations in circulating NP as compared to those associated with sham-RDN. Further investigation into the cause of increased circulating NP levels demonstrated that RF-RDN significantly inhibited renal neprilysin activity in SHR and WKY with HF. Likewise, chronic treatment with the beta1 antagonist bisoprolol inhibited renal neprilysin activity and increased circulation NP levels in WKY with HF. CONCLUSIONS: This study identifies a novel endogenous pathway by which the renal nerves participate in the degradation of cardioprotective NP. Furthermore, removal of the influence of the renal nerves on kidney function attenuates renal neprilysin activity, augments circulating NP levels, reduces myocardial fibrosis, and improves LV function in the setting of HF.


Asunto(s)
Insuficiencia Cardíaca/terapia , Riñón/inervación , Neprilisina/antagonistas & inhibidores , Simpatectomía , Aminobutiratos/farmacología , Angiotensina II/sangre , Animales , Compuestos de Bifenilo , Bisoprolol/farmacología , Presión Sanguínea , Combinación de Medicamentos , Ecocardiografía , Miocardio/química , Miocardio/patología , Neprilisina/fisiología , Nitritos/análisis , Norepinefrina/sangre , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Arteria Renal/inervación , Renina/sangre , Daño por Reperfusión/fisiopatología , Tetrazoles/farmacología , Valsartán , Función Ventricular Izquierda/fisiología
10.
J Am Heart Assoc ; 5(7)2016 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-27381758

RESUMEN

BACKGROUND: Zofenopril, a sulfhydrylated angiotensin-converting enzyme inhibitor (ACEI), reduces mortality and morbidity in infarcted patients to a greater extent than do other ACEIs. Zofenopril is a unique ACEI that has been shown to increase hydrogen sulfide (H2S) bioavailability and nitric oxide (NO) levels via bradykinin-dependent signaling. Both H2S and NO exert cytoprotective and antioxidant effects. We examined zofenopril effects on H2S and NO bioavailability and cardiac damage in murine and swine models of myocardial ischemia/reperfusion (I/R) injury. METHODS AND RESULTS: Zofenopril (10 mg/kg PO) was administered for 1, 8, and 24 hours to establish optimal dosing in mice. Myocardial and plasma H2S and NO levels were measured along with the levels of H2S and NO enzymes (cystathionine ß-synthase, cystathionine γ-lyase, 3-mercaptopyruvate sulfur transferase, and endothelial nitric oxide synthase). Mice received 8 hours of zofenopril or vehicle pretreatment followed by 45 minutes of ischemia and 24 hours of reperfusion. Pigs received placebo or zofenopril (30 mg/daily orally) 7 days before 75 minutes of ischemia and 48 hours of reperfusion. Zofenopril significantly augmented both plasma and myocardial H2S and NO levels in mice and plasma H2S (sulfane sulfur) in pigs. Cystathionine ß-synthase, cystathionine γ-lyase, 3-mercaptopyruvate sulfur transferase, and total endothelial nitric oxide synthase levels were unaltered, while phospho-endothelial nitric oxide synthase(1177) was significantly increased in mice. Pretreatment with zofenopril significantly reduced myocardial infarct size and cardiac troponin I levels after I/R injury in both mice and swine. Zofenopril also significantly preserved ischemic zone endocardial blood flow at reperfusion in pigs after I/R. CONCLUSIONS: Zofenopril-mediated cardioprotection during I/R is associated with an increase in H2S and NO signaling.


Asunto(s)
Antihipertensivos/farmacología , Captopril/análogos & derivados , Corazón/efectos de los fármacos , Sulfuro de Hidrógeno/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Miocardio/metabolismo , Óxido Nítrico/metabolismo , Animales , Disponibilidad Biológica , Western Blotting , Captopril/farmacología , Cistationina betasintasa/efectos de los fármacos , Cistationina betasintasa/genética , Cistationina betasintasa/metabolismo , Cistationina gamma-Liasa/efectos de los fármacos , Cistationina gamma-Liasa/genética , Cistationina gamma-Liasa/metabolismo , Ratones , Infarto del Miocardio/patología , Miocardio/patología , Óxido Nítrico Sintasa de Tipo III/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ramipril/farmacología , Distribución Aleatoria , Flujo Sanguíneo Regional , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sulfurtransferasas/efectos de los fármacos , Sulfurtransferasas/genética , Sulfurtransferasas/metabolismo , Porcinos , Porcinos Enanos , Troponina I/efectos de los fármacos , Troponina I/metabolismo
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