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Aim: Recent studies demonstrate that sodium-glucose cotransporter 2 inhibitors (SGLT2i) and dipeptidyl peptidase-4 inhibitors (DPP4i), two classes of antidiabetic drugs, are cardioprotective. However, the mechanisms of these benefits and their comparative efficacy remain unclear. We aimed to compare the effects of these antidiabetic agents on cardiac function, perfusion, and microvascular density using a swine model of chronic myocardial ischemia. Methods: Chronic myocardial ischemia was induced in Yorkshire swine by ameroid constrictor placement to the left circumflex artery. Two weeks later, pigs were administered vehicle ("CON", 8 pigs), 300 mg SGLT2i canagliflozin, ("CANA", 8 pigs), or 100 mg DPP4i sitagliptin ("SIT", 5 pigs) daily. Five weeks later, pigs were euthanized. Cardiac function, perfusion, collateralization, and protein expression were determined by pressure-volume catheter, microsphere analysis, immunofluorescence, and immunoblotting, respectively. Results: Compared with SIT, CANA was associated with improved stroke volume and cardiac output, with a trend towards reduced left ventricular stiffness. Both CANA and SIT trended towards improved perfusion compared to CON, but there were no differences between the two treatment groups. SIT was associated with improved capillary density with a trend towards improved arteriolar density compared to CANA. Both CANA and SIT were associated with increased expression of vascular endothelial cadherin compared to CON, without differences in treatment groups. SIT pigs had decreased 5' adenosine monophosphate-activated protein kinase activation compared to CON and CANA. There was a trend towards increased endothelial nitric oxide synthase activation in the SIT group compared to CON. There were no differences in activation of extracellular signal-regulated kinase 1/2 across groups. Conclusions: In the setting of chronic myocardial ischemia, canagliflozin is associated with improved cardiac function compared to sitagliptin, with similar effects on perfusion despite differences in microvascular collateralization.
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Objective: Coronary artery disease (CAD) is the leading cause of death worldwide. It imposes an enormous symptomatic burden on patients, leaving many with residual disease despite optimal procedural therapy, and up to 1/3 with debilitating angina amenable neither to procedures, nor to current pharmacologic options. Semaglutide, a glucagon-like peptide 1 agonist originally approved for management of diabetes, has garnered substantial attention for its capacity to attenuate cardiovascular risk. Although subgroup analyses in patients indicate promise, studies explicitly designed to isolate the impact of semaglutide on the sequelae of CAD, independently of comorbid diabetes or obesity, are lacking. Approach and Results: Yorkshire swine (n=17) underwent placement of an ameroid constrictor around the left circumflex coronary artery to induce CAD. Oral semaglutide was initiated postoperatively at 1.5 mg and scaled up in 2 weeks to 3 mg in treatment animals (SEM, n=8) for a total of 5 weeks, while control animals (CON, n=9) received no drug. All then underwent myocardial harvest with acquisition of perfusion and functional data using microsphere injection and pressure-volume loop catheterization. Immunoblotting, immunohistochemistry, and immunofluorescence were performed on the most ischemic myocardial segments for mechanistic elucidation. SEM animals exhibited improved left ventricular ejection fraction, both at rest and during rapid myocardial pacing (both p<0.03), accompanied by increased perfusion to the most ischemic myocardial region at rest and during rapid pacing (both p<0.03); reduced perivascular and interstitial fibrosis (both p <0.03); and apoptosis (p=0.008). These changes were associated with increased activation of the endothelial-protective AMPK pathway (p=0.005), coupled with downstream increases in endothelial nitric oxide synthase (p=0.014). Conclusion: This study is the first to reveal the capacity of oral semaglutide to augment cardiac function in the chronically ischemic heart in a highly translational large animal model, likely through AMPK-mediated improvement in endothelial function and perfusion to the ischemic myocardium.
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Cardiopulmonary bypass (CPB) initiates an intense inflammatory response due to various factors: conversion from pulsatile to laminar flow, cold cardioplegia, surgical trauma, endotoxemia, ischemia-reperfusion injury, oxidative stress, hypothermia, and contact activation of cells by the extracorporeal circuit. Redundant and overlapping inflammatory cascades amplify the initial response to produce a systemic inflammatory response, heightened by coincident activation of coagulation and fibrinolytic pathways. When unchecked, this inflammatory response can become maladaptive and lead to serious postoperative complications. Concerted research efforts have been made to identify technical refinements and pharmacologic interventions that appropriately attenuate the inflammatory response and ultimately translate to improved clinical outcomes. Surface modification of the extracorporeal circuit to increase biocompatibility, miniaturized circuits with sheer resistance, filtration techniques, and minimally invasive approaches have improved clinical outcomes in specific populations. Pharmacologic adjuncts, including aprotinin, steroids, monoclonal antibodies, and free radical scavengers, show real promise. A multimodal approach incorporating technical, circuit-specific, and pharmacologic strategies will likely yield maximal clinical benefit.
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Although both clinical data and animal models suggest cardiovascular benefits following administration of Dipeptidyl Peptidase 4 (DPP-4) inhibitors, the underlying mechanisms remain unclear. We therefore sought to evaluate the effect of the DPP-4 inhibitor sitagliptin on myocardial fibrosis, and insulin signaling in chronic myocardial ischemia using a swine model. An ameroid constrictor placement on the left coronary circumflex artery of thirteen Yorkshire swine to model chronic myocardial ischemia. After two weeks of recovery, swine were assigned to one of two groups: control (CON, n = 8), or sitagliptin 100mg daily (SIT, n = 5). After 5 weeks of treatment, the swine underwent terminal harvest with collection of myocardial tissue. Fibrosis was quantified using Masson's trichrome. Protein expression was quantified by Immunoblotting. Trichrome stain demonstrated a significant decrease in perivascular and interstitial fibrosis in the SIT group relative to CON (all p<0.05). Immunoblot showed a reduction in Jak2, the pSTAT3 to STAT 3 Ratio, pSMAD 2/3, and SMAD 2/3, and an increase in STAT 3 in the SIT group relative to CON (all p<0.05). SIT treatment was associated with increased expression of insulin receptor one and decreased expression of makers for insulin resistance, including phospho-PKC- alpha, RBP-4, SIRT1, and PI3K (p<0.05). Sitagliptin results in a reduction in perivascular and interstitial fibrosis and increased insulin sensitivity in chronically ischemic swine myocardium. This likely contributes to the improved cardiovascular outcomes seen with DPP-4 inhibitors.
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Inibidores da Dipeptidil Peptidase IV , Modelos Animais de Doenças , Fibrose , Insulina , Isquemia Miocárdica , Miocárdio , Transdução de Sinais , Fosfato de Sitagliptina , Animais , Fosfato de Sitagliptina/farmacologia , Fosfato de Sitagliptina/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Insulina/metabolismo , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/patologia , Suínos , Miocárdio/metabolismo , Miocárdio/patologia , Doença CrônicaRESUMO
OBJECTIVE: To test the efficacy of metformin during the induction of coronary ischemia on myocardial performance in a large animal model of coronary artery disease (CAD) and metabolic syndrome (MS), with or without concomitant extracellular vesicular (EV) therapy. BACKGROUND: Although surgical and endovascular revascularization are durably efficacious for many patients with CAD, up to one-third are poor candidates for standard therapies. For these patients, many of whom have comorbid MS, adjunctive strategies are needed. EV therapy has shown promise in this context, but its efficacy is attenuated by MS. We investigated whether metformin pretreatment could ameliorate therapeutic decrements associated with MS. METHODS: Yorkshire swine (n=29) were provided a high-fat diet to induce MS, whereupon an ameroid constrictor was placed to induce CAD. Animals were initiated on 1000 mg PO metformin or placebo; all then underwent repeat thoracotomy for intramyocardial injection of EVs or saline. Swine were maintained for five weeks before acquisition of functional and perfusion data immediately prior to terminal myocardial harvest. Immunoblotting and immunofluorescence were performed on the most ischemic tissue from all groups. RESULTS: Regardless of EV administration, animals that received metformin exhibited significantly improved ejection fraction, cardiac index, and contractility at rest and during rapid myocardial pacing; improved perfusion to the most ischemic myocardial region at rest and during pacing; and markedly reduced apoptosis. CONCLUSIONS: Metformin administration reduced apoptotic cell death, improved perfusion, and augmented both intrinsic and load-dependent myocardial performance in a highly translatable large animal model of chronic myocardial ischemia and metabolic syndrome.
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INTRODUCTION: Sodium-glucose cotransporter-2 inhibitors are antidiabetic medications that have been shown to decrease cardiovascular events and heart failure-related mortality in clinical studies. We attempt to examine the complex interplay between metabolic syndrome and the sodium-glucose cotransporter-2 inhibitor canagliflozin (CAN) in a clinically relevant model of chronic myocardial ischemia. METHODS: Twenty-one Yorkshire swine were fed a high-fat diet starting at 6 weeks of age to induce metabolic syndrome. At 11 weeks, all underwent placement of an ameroid constrictor around the left circumflex coronary artery to induce chronic myocardial ischemia. After 2 weeks, swine received either control (CON) (n = 11) or CAN 300 mg by mouth daily (n = 10) for 5 weeks, whereupon all underwent terminal harvest. RESULTS: There was a significant increase in cardiac output and heart rate with a decrease in pulse pressure in the CAN group compared with CON (all P values < .05). The CAN group had a significant increase in capillary density (P = .02). There was no change in myocardial perfusion or arteriolar density. CAN induced a significant increase in markers of angiogenesis, including Phospho-endothelial nitric oxide synthase, Endothelial nitric oxide synthase, vascular endothelial growth factor receptor-1, heat shock protein 70, and extracellular signal-regulated kinases (all P values < .05), plausibly resulting in capillary angiogenesis. CONCLUSIONS: CAN treatment leads to a significant increase in capillary density and augmented cardiac function in a swine model of chronic myocardial ischemia in the setting of metabolic syndrome. This work further elucidates the mechanism of sodium-glucose cotransporter-2 inhibitors in patients with cardiac disease; however, more studies are needed to determine if this increase in capillary density plays a role in the improvements seen in clinical studies.
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Since the invention of cardiopulmonary bypass, cardioprotective strategies have been investigated to mitigate ischemic injury to the heart during aortic cross-clamping and reperfusion injury with cross-clamp release. With advances in cardiac surgical and percutaneous techniques and post-operative management strategies including mechanical circulatory support, cardiac surgeons are able to operate on more complex patients. Therefore, there is a growing need for improved cardioprotective strategies to optimize outcomes in these patients. This review provides an overview of the basic principles of cardioprotection in the setting of cardiac surgery, including mechanisms of cardiac injury in the context of cardiopulmonary bypass, followed by a discussion of the specific approaches to optimizing cardioprotection in cardiac surgery, including refinements in cardiopulmonary bypass and cardioplegia, ischemic conditioning, use of specific anesthetic and pharmaceutical agents, and novel mechanical circulatory support technologies. Finally, translational strategies that investigate cardioprotection in the setting of cardiac surgery will be reviewed, with a focus on promising research in the areas of cell-based and gene therapy. Advances in this area will help cardiologists and cardiac surgeons mitigate myocardial ischemic injury, improve functional post-operative recovery, and optimize clinical outcomes in patients undergoing cardiac surgery.
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Traumatismo por Reperfusão Miocárdica , Humanos , Animais , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Precondicionamento Isquêmico Miocárdico/métodos , Cardiotônicos/uso terapêutico , Ponte Cardiopulmonar/efeitos adversosRESUMO
BACKGROUND: We previously found that cardioplegic arrest and cardiopulmonary bypass are associated with altered coronary arteriolar response to serotonin in patients undergoing cardiac surgery. In this study, we investigated the effects of hypertension on coronary microvascular vasomotor tone in response to serotonin and alterations in serotonin receptor protein expression in the setting of cardioplegic arrest and cardiopulmonary bypass. METHODS: Coronary arterioles were dissected from harvested pre- and post-cardioplegic arrest and cardiopulmonary bypass right atrial tissue samples of patients undergoing cardiac surgery with normotension, well-controlled hypertension, and uncontrolled hypertension. Vasomotor tone was assessed by video-myography, and protein expression was measured with immunoblotting. RESULTS: Pre-cardioplegic arrest and cardiopulmonary bypass, serotonin induced moderate relaxation responses of coronary arterioles in normotension and well-controlled hypertension patients, whereas serotonin caused moderate contractile responses in uncontrolled hypertension patients. Post-cardioplegic arrest and cardiopulmonary bypass, serotonin caused contractile responses of coronary arterioles in all 3 groups. The post-cardioplegic arrest and cardiopulmonary bypass contractile response to serotonin was significantly higher in the uncontrolled hypertension group compared with the normotension or well-controlled hypertension groups (P < .05). Pre-cardioplegic arrest and cardiopulmonary bypass, expression of the serotonin 1A receptor was significantly lower in the uncontrolled hypertension group compared with the well-controlled hypertension and normotension groups (P = .01 and P < .001). Serotonin 1B receptor expression was higher in the uncontrolled hypertension group compared with the normotension or well-controlled hypertension groups post-cardioplegic arrest and cardiopulmonary bypass (P = .03 and P = .046). CONCLUSION: Uncontrolled hypertension is associated with an increased coronary contractile response of coronary microvessels to serotonin and altered serotonin receptor protein expression after cardioplegic arrest and cardiopulmonary bypass. These findings may contribute to a worse postoperative coronary spasm and worsened recovery of coronary perfusion in patients with uncontrolled hypertension after cardioplegic arrest and cardiopulmonary bypass and cardiac surgery.
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Ponte Cardiopulmonar , Vasos Coronários , Hipertensão , Serotonina , Humanos , Ponte Cardiopulmonar/efeitos adversos , Masculino , Feminino , Serotonina/metabolismo , Serotonina/farmacologia , Hipertensão/fisiopatologia , Hipertensão/metabolismo , Hipertensão/etiologia , Pessoa de Meia-Idade , Idoso , Vasos Coronários/fisiopatologia , Arteríolas/metabolismo , Arteríolas/fisiopatologia , Arteríolas/efeitos dos fármacos , Parada Cardíaca Induzida/efeitos adversos , Vasoconstrição/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Vasodilatação/efeitos dos fármacosRESUMO
Dysfunction of the coronary microvasculature has become increasingly recognized as an important mechanism of myocardial ischemia in patients without obstructive coronary artery disease. The causes and management of coronary microvascular dysfunction remain poorly understood and are still largely based on extrapolation of epicardial coronary artery disease data. Quantification of myocardial blood flow and flow reserve have improved diagnosis, though important questions remain. In this review, we explain current understanding of the spectrum of pathophysiology of coronary microvascular dysfunction, summarize current diagnostic techniques to assess for coronary microvascular dysfunction, and appraise the limited data on management options specifically for patients with coronary microvascular dysfunction.
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Circulação Coronária , Microcirculação , Humanos , Circulação Coronária/fisiologia , Microcirculação/fisiologia , Microvasos/fisiopatologia , Vasos Coronários/fisiopatologia , Vasos Coronários/diagnóstico por imagem , Isquemia Miocárdica/fisiopatologia , Isquemia Miocárdica/diagnóstico , Doença da Artéria Coronariana/fisiopatologia , Doença da Artéria Coronariana/diagnósticoRESUMO
Gastrointestinal complications after cardiac surgery are relatively rare entities but carry a high mortality. We identified over 70 articles written since 2010 using the PubMed database. We included 40 in our review. The most common complications include paralytic ileus, gastrointestinal bleeding, and bowel ischemia. Patients who undergo cardiac procedures are at risk for poor perfusion of the gastrointestinal tract and, thus, at risk for resulting complications. Risk factors for these complications include peri-operative use of vasopressors, prolonged operative time, and the time of cardiopulmonary bypass. Presentation of gastrointestinal complications tends to differ as patients after open heart surgery can remain intubated, and exams can be limited. Early recognition and aggressive therapy are paramount. We aim to provide a review that will help the reader get familiar with the most common gastrointestinal complications that can negatively affect outcomes after cardiac surgery.
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Small animal models have shown improved cardiac function with DPP-4 inhibition, but many human studies have shown worse outcomes or no benefit. We seek to bridge the gap by studying the DPP-4 inhibitor sitagliptin in a swine model of chronic myocardial ischemia using proteomic analysis. Thirteen Yorkshire swine underwent the placement of an ameroid constrictor on the left coronary circumflex artery to model chronic myocardial ischemia. Two weeks post-op, swine received either sitagliptin 100 mg daily (SIT, n = 5) or no drug (CON, n = 8). After 5 weeks of treatment, swine underwent functional measurements and tissue harvest. In the SIT group compared to CON, there was a trend towards decreased cardiac index (p = 0.06). The non-ischemic and ischemic myocardium had 396 and 166 significantly decreased proteins, respectively, in the SIT group compared to CON (all p < 0.01). This included proteins involved in fatty acid oxidation (FAO), myocardial contraction, and oxidative phosphorylation (OXPHOS). Sitagliptin treatment resulted in a trend towards decreased cardiac index and decreased expression of proteins involved in OXPHOS, FAO, and myocardial contraction in both ischemic and non-ischemic swine myocardium. These metabolic and functional changes may provide some mechanistic evidence for outcomes seen in clinical studies.
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Inibidores da Dipeptidil Peptidase IV , Isquemia Miocárdica , Suínos , Humanos , Animais , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Proteoma/metabolismo , Fosforilação Oxidativa , Fosfato de Sitagliptina/uso terapêutico , Proteômica/métodos , Miocárdio/metabolismo , Hipoglicemiantes/uso terapêutico , Modelos Animais de DoençasRESUMO
Cardiovascular disease (CVD) remains the leading cause of mortality worldwide. In particular, patients who suffer from ischemic heart disease (IHD) that is not amenable to surgical or percutaneous revascularization techniques have limited treatment options. Furthermore, after revascularization is successfully implemented, there are a number of pathophysiological changes to the myocardium, including but not limited to ischemia-reperfusion injury, necrosis, altered inflammation, tissue remodeling, and dyskinetic wall motion. Electrospinning, a nanofiber scaffold fabrication technique, has recently emerged as an attractive option as a potential therapeutic platform for the treatment of cardiovascular disease. Electrospun scaffolds made of biocompatible materials have the ability to mimic the native extracellular matrix and are compatible with drug delivery. These inherent properties, combined with ease of customization and a low cost of production, have made electrospun scaffolds an active area of research for the treatment of cardiovascular disease. In this review, we aim to discuss the current state of electrospinning from the fundamentals of scaffold creation to the current role of electrospun materials as both bioengineered extracellular matrices and drug delivery vehicles in the treatment of CVD, with a special emphasis on the potential clinical applications in myocardial ischemia.
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BACKGROUND: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are known to be cardioprotective independent of glucose control, but the mechanisms of these benefits are unclear. We previously demonstrated improved cardiac function and decreased fibrosis in a swine model of chronic myocardial ischemia. The goal of this study is to use high-sensitivity proteomic analyses to characterize specific molecular pathways affected by SGLT-2 inhibitor canagliflozin (CAN) therapy in a swine model of chronic myocardial ischemia. METHODS: Chronic myocardial ischemia was induced in sixteen Yorkshire swine via the placement of an ameroid constrictor to the left circumflex coronary artery. After two weeks of recovery, swine received either 300 mg of CAN daily (n = 8) or a control (n = 8). After five weeks of therapy, the group of swine were euthanized, and left ventricular tissue was harvested and sent for proteomic analysis. RESULTS: Total proteomic analysis identified a total of 3256 proteins between the CAN and control groups. Three hundred and five proteins were statistically different. This included 55 proteins that were downregulated (p < 0.05, fold change <0.5) and 250 that were upregulated (p < 0.05, fold change >2) with CAN treatment. Pathway analysis demonstrated the upregulation of several proteins involved in metabolism and redox activity in the CAN-treated group. The CAN group also exhibited a downregulation of proteins involved in motor activity and cytoskeletal structure. CONCLUSIONS: In our swine model of chronic myocardial ischemia, CAN therapy alters several proteins involved in critical molecular pathways, including redox regulation and metabolism. These findings provide additional mechanistic insights into the cardioprotective effects of canagliflozin.
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INTRODUCTION: Patients with advanced coronary artery disease (CAD) who are not eligible for stenting or surgical bypass procedures have limited treatment options. Extracellular vesicles (EVs) have emerged as a potential therapeutic target for the treatment of advanced CAD. These EVs can be conditioned to modify their contents. In our previous research, we demonstrated increased perfusion, decreased inflammation, and reduced apoptosis with intramyocardial injection of hypoxia-conditioned EVs (HEVs). The goal of this study is to further understand the function of HEVs by examining their impact on oxidative stress using our clinically relevant and extensively validated swine model of chronic myocardial ischemia. METHODS: Fourteen Yorkshire swine underwent a left thoracotomy for the placement of an ameroid constrictor on the left circumflex coronary artery to model chronic myocardial ischemia. After two weeks of recovery, the swine underwent a redo thoracotomy with injection of either HEVs (n = 7) or a saline control (CON, n = 7) into the ischemic myocardium. Five weeks after injection, the swine were subjected to terminal harvest. Protein expression was measured using immunoblotting. OxyBlot analysis and 3-nitrotyrosine staining were used to quantify total oxidative stress. RESULTS: There was a significant increase in myocardial expression of the antioxidants SOD 2, GPX-1, HSF-1, UCP-2, catalase, and HO-1 (all p ≤ 0.05) in the HEV group when compared to control animals. The HEVs also exhibited a significant increase in pro-oxidant NADPH oxidase (NOX) 1, NOX 3, p47phox, and p67phox (all p ≤ 0.05). However, no change was observed in the expression of NFkB, KEAP 1, and PRDX1 (all p > 0.05) between the HEV and CON groups. There were no significant differences in total oxidative stress as determined by OxyBlot and 3-nitrotyrosine staining (p = 0.64, p = 0.32) between the groups. CONCLUSIONS: Administration of HEVs in ischemic myocardium induces a significant increase in pro- and antioxidant proteins without a net change in total oxidative stress. These findings suggest that HEV-induced changes in redox signaling pathways may play a role in increased perfusion, decreased inflammation, and reduced apoptosis in ischemic myocardium. Further studies are required to determine if HEVs alter the net oxidative stress in ischemic myocardium at an earlier time point of HEV administration.
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The past several decades have borne witness to several breakthroughs and paradigm shifts within the field of cardiovascular medicine, but one component that has remained constant throughout this time is the need for accurate animal models for the refinement and elaboration of the hypotheses and therapies crucial to our capacity to combat human disease. Numerous sophisticated and high-throughput molecular strategies have emerged, including rational drug design and the multi-omics approaches that allow extensive characterization of the host response to disease states and their prospective resolutions, but these technologies all require grounding within a faithful representation of their clinical context. Over this period, our lab has exhaustively tested, progressively refined, and extensively contributed to cardiovascular discovery on the basis of one such faithful representation. It is the purpose of this paper to review our porcine model of chronic myocardial ischemia using ameroid constriction and the subsequent myriad of physiological and molecular-biological insights it has allowed our lab to attain and describe. We hope that, by depicting our methods and the insight they have yielded clearly and completely-drawing for this purpose on comprehensive videographic illustration-other research teams will be empowered to carry our work forward, drawing on our experience to refine their own investigations into the pathogenesis and eradication of cardiovascular disease.
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The extracellular matrix (ECM) is a three-dimensional, acellular network of diverse structural and nonstructural proteins embedded within a gel-like ground substance composed of glycosaminoglycans and proteoglycans. The ECM serves numerous roles that vary according to the tissue in which it is situated. In the myocardium, the ECM acts as a collagen-based scaffold that mediates the transmission of contractile signals, provides means for paracrine signaling, and maintains nutritional and immunologic homeostasis. Given this spectrum, it is unsurprising that both the composition and role of the ECM has been found to be modulated in the context of cardiac pathology. Myocardial infarction (MI) provides a familiar example of this; the ECM changes in a way that is characteristic of the progressive phases of post-infarction healing. In recent years, this involvement in infarct pathophysiology has prompted a search for therapeutic targets: if ECM components facilitate healing, then their manipulation may accelerate recovery, or even reverse pre-existing damage. This possibility has been the subject of numerous efforts involving the integration of ECM-based therapies, either derived directly from biologic sources or bioengineered sources, into models of myocardial disease. In this paper, we provide a thorough review of the published literature on the use of the ECM as a novel therapy for ischemic heart disease, with a focus on biologically derived models, of both the whole ECM and the components thereof.
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Infarto do Miocárdio , Isquemia Miocárdica , Humanos , Matriz Extracelular , Coração , Infarto do Miocárdio/terapia , Isquemia Miocárdica/terapia , MiocárdioRESUMO
BACKGROUND: Small conductance calcium-activated potassium (SK) channels are largely responsible for endothelium-dependent coronary arteriolar relaxation. Endothelial SK channels are downregulated by the reduced form of nicotinamide adenine dinucleotide (NADH), which is increased in the setting of diabetes, yet the mechanisms of these changes are unclear. PKC (protein kinase C) is an important mediator of diabetes-induced coronary endothelial dysfunction. Thus, we aimed to determine whether NADH signaling downregulates endothelial SK channel function via PKC. METHODS AND RESULTS: SK channel currents of human coronary artery endothelial cells were measured by whole cell patch clamp method in the presence/absence of NADH, PKC activator phorbol 12-myristate 13-acetate, PKC inhibitors, or endothelial PKCα/PKCß knockdown by using small interfering RNA. Human coronary arteriolar reactivity in response to the selective SK activator NS309 was measured by vessel myography in the presence of NADH and PKCß inhibitor LY333531. NADH (30-300 µmol/L) or PKC activator phorbol 12-myristate 13-acetate (30-300 nmol/L) reduced endothelial SK current density, whereas the selective PKCᵦ inhibitor LY333531 significantly reversed the NADH-induced SK channel inhibition. PKCß small interfering RNA, but not PKCα small interfering RNA, significantly prevented the NADH- and phorbol 12-myristate 13-acetate-induced SK inhibition. Incubation of human coronary artery endothelial cells with NADH significantly increased endothelial PKC activity and PKCß expression and activation. Treating vessels with NADH decreased coronary arteriolar relaxation in response to the selective SK activator NS309, and this inhibitive effect was blocked by coadministration with PKCß inhibitor LY333531. CONCLUSIONS: NADH-induced inhibition of endothelial SK channel function is mediated via PKCß. These findings may provide insight into novel therapeutic strategies to preserve coronary microvascular function in patients with metabolic syndrome and coronary disease.
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Diabetes Mellitus , Forbóis , Humanos , Canais de Potássio Ativados por Cálcio de Condutância Baixa/metabolismo , Proteína Quinase C beta/metabolismo , Proteína Quinase C beta/farmacologia , Células Endoteliais/metabolismo , Miristatos/metabolismo , Miristatos/farmacologia , NAD/metabolismo , Vasodilatação/fisiologia , Diabetes Mellitus/metabolismo , Endotélio Vascular/metabolismo , RNA Interferente Pequeno/metabolismo , Acetatos/metabolismo , Acetatos/farmacologia , Forbóis/metabolismo , Forbóis/farmacologiaRESUMO
BACKGROUND: Although sodium-glucose cotransporter-2 inhibitors have been shown to improve cardiovascular outcomes in general, little is presently known about any sex-specific changes that may result from this therapy. We sought to investigate and quantify potential sex-specific changes seen with the sodium-glucose cotransporter-2 inhibitor canagliflozin (CAN) in a swine model of chronic myocardial ischemia. STUDY DESIGN: Eighteen Yorkshire swine underwent left thoracotomy with placement of an ameroid constrictor. Two weeks postop, swine were assigned to receive either control (F = 5 and M = 5) or CAN 300 mg daily (F = 4 and M = 4). After 5 weeks of therapy, swine underwent myocardial functional measurements, and myocardial tissue was sent for proteomic analysis. RESULTS: Functional measurements showed increased cardiac output, stroke volume, ejection fraction, and ischemic myocardial flow at rest in male swine treated with CAN compared with control male swine (all p < 0.05). The female swine treated with CAN had no change in cardiac function as compared with control female swine. Proteomic analysis demonstrated 6 upregulated and 97 downregulated proteins in the CAN female group compared with the control female group. Pathway analysis showed decreases in proteins in the tricarboxylic acidic cycle. The CAN male group had 639 upregulated and 172 downregulated proteins compared with control male group. Pathway analysis showed increases in pathways related to cellular metabolism and decreases in pathways relevant to the development of cardiomyopathy and to oxidative phosphorylation. CONCLUSIONS: Male swine treated with CAN had significant improvements in cardiac function that were not observed in female swine treated with CAN. Moreover, CAN treatment in male swine was associated with significantly more changes in protein expression than in female swine treated with CAN. The increased proteomic changes seen in the CAN male group likely contributed to the more robust changes in cardiac function seen in male swine treated with CAN.
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Canagliflozina , Isquemia Miocárdica , Proteômica , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Feminino , Masculino , Canagliflozina/farmacologia , Canagliflozina/uso terapêutico , Doença Crônica , Modelos Animais de Doenças , Isquemia Miocárdica/metabolismo , Miocárdio/metabolismo , Fatores Sexuais , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , SuínosRESUMO
Angiogenesis, the process of new blood vessels formation from existing vasculature, plays a vital role in development, wound healing, and various pathophysiological conditions. In recent years, extracellular vesicles (EVs) have emerged as crucial mediators in intercellular communication and have gained significant attention for their role in modulating angiogenic processes. This review explores the multifaceted role of EVs in angiogenesis and their capacity to modulate angiogenic signaling pathways. Through comprehensive analysis of a vast body of literature, this review highlights the potential of utilizing EVs as therapeutic tools to modulate angiogenesis for both physiological and pathological purposes. A good understanding of these concepts holds promise for the development of novel therapeutic interventions targeting angiogenesis-related disorders.
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Angiogênese , Vesículas Extracelulares , Transdução de Sinais , Comunicação Celular , Fenômenos Fisiológicos CardiovascularesRESUMO
BACKGROUND: Inflammation and disruption of cardiac metabolism are prevalent in the setting of myocardial ischemia. Canagliflozin, a sodium-glucose costransporter-2 inhibitor, has beneficial effects on the heart, though the precise mechanisms are unknown. This study investigated the effects of canagliflozin therapy on metabolic pathways and inflammation in ischemic myocardial tissue using a swine model of chronic myocardial ischemia. METHODS: Sixteen Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic ischemia. Two weeks later, pigs received either no drug (n = 8) or 300 mg canagliflozin (n = 8) daily. Five weeks later, pigs underwent terminal harvest and tissue collection. RESULTS: Canagliflozin treatment was associated with a trend toward decreased expression of fatty acid oxidation inhibitor acetyl-CoA carboxylase and decreased phosphorylated/inactivated acetyl-CoA carboxylase, a promotor of fatty acid oxidation, compared with control ischemic myocardium (P = .08, P = .03). There was also a significant modulation in insulin resistance markers p-IRS1, p-PKCα, and phosphoinositide 3-kinase in ischemic myocardium of the canagliflozin group compared with the control group (all P < .05). Canagliflozin treatment was associated with a significant increase in inflammatory markers interleukin 6, interleukin 17, interferon-gamma, and inducible nitric oxide synthase (all P < .05). There was a trend toward decreased expression of the anti-inflammatory cytokines interleukin 10 (P = .16) and interleukin 4 (P = .31) with canagliflozin treatment. CONCLUSION: The beneficial effects of canagliflozin therapy appear to be associated with inhibition of fatty acid oxidation and enhancement of insulin signaling in ischemic myocardium. Interestingly, canagliflozin appears to increase the levels of several inflammatory markers, but further studies are required to better understand how canagliflozin modulates inflammatory signaling pathways.