Article

Local infiltration of Neuropeptide Y as a potential therapeutic agent against apoptosis and fibrosis in a swine model of hypercholesterolemia and chronic myocardial ischemia.

Beth Israel Deaconess Medical Center, Department of Anesthesia and Critical Care
European journal of pharmacology (Impact Factor: 2.53). 09/2013; 718(1-3). DOI: 10.1016/j.ejphar.2013.08.023
Source: PubMed

ABSTRACT

While the angiogenic effects of Neuropeptide Y (NPY) in myocardial ischemia and hypercholesterolemia have been studied, its effects on altering oxidative stress, fibrosis and cell death are not known. We hypothesized that local infiltration of NPY in a swine model of chronic myocardial ischemia and hypercholesterolemia will induce nerve growth and cell survival, while reducing oxidative stress and fibrosis. Yorkshire mini-swine (n=15) were fed a high cholesterol diet for five weeks. Three weeks after surgical induction of focal myocardial ischemia, an osmotic pump was implanted, which delivered NPY (n=8, high cholesterol treated, HCT) or the vehicle (n=7, high cholesterol control, HCC) for five weeks. Then myocardium was harvested for analysis. Assessment of myocardial function and perfusion was made the last intervention. Immunoblotting demonstrated significantly decreased levels of MMP-9 (p=0.001) and TGF-β (p=0.05) and significantly increased levels of Ang-1 (p=0.002), MnSOD (p=0.006) and NGF (p=0.01) in HCT. Immunohistochemistry results revealed significantly decreased TUNEL staining (p=0.005) and GLUT4 translocation (p=0.004) in HCT. The functional data showed significantly improved blood flow reserve (p=0.02) and improved diastolic function -dP/dt (p=0.009) in the treated animals. Local infiltration of NPY results in positive remodeling in ischemic myocardium in the setting of hypercholesterolemia. By initiating angio and neurogenesis, NPY infiltration improves blood flow reserve and restoration of fatty acid metabolism. The associated increased cell survival and decreased fibrosis results in improved myocardial diastolic function. NPY may have a potential therapeutic role in patients with hypercholesterolemia associated coronary artery disease.

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    • "NPY initiated angiogenesis leads to improved vascular reserve and less oxidative stress on the mitochondria thus shifting cellular metabolism back to fatty acid oxidation and increasing markers of cell survival. The NPY related remodeling led to neurogenesis and angiogenesis possibly causing increased cell survival and decreased fibrosis thus improving diastolic function [42]. Majority of above mentioned measurements have been done in acute phase of ischemia. "
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    ABSTRACT: The role of neuropeptides in cardiomyopathy-associated heart failure has been garnering more attention. Several neuropeptides - Neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), calcitonin gene related peptide (CGRP), substance P (SP) and their receptors have been studied in the various types of cardiomyopathies. The data indicate associations with the strength of the association varying depending on the kind of neuropeptide and the nature of the cardiomyopathy-diabetic, ischemic, inflammatory, stress-induced or restricitive cardiomyopathy. Several neuropeptides appear to alter regulation of genes involved in heart failure. Demonstration of an association is an essential first step in proving causality or establishing a role for a factor in a disease. Understanding the complexity of neuropeptide function should be helpful in establishing new or optimal therapeutic strategies for the treatment of heart failure in cardiomyopathies.
    Full-text · Article · Aug 2014 · Peptides
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    • "NPY initiated angiogenesis leads to improved vascular reserve and less oxidative stress on the mitochondria thus shifting cellular metabolism back to fatty acid oxidation and increasing markers of cell survival. The NPY related remodeling led to neurogenesis and angiogenesis possibly causing increased cell survival and decreased fibrosis thus improving diastolic function [42]. Majority of above mentioned measurements have been done in acute phase of ischemia. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The role of neuropeptides in cardiomyopathy-associated heart failure has been garnering more attention. Several neuropeptides - Neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), calcitonin gene related peptide (CGRP), substance P (SP) and their receptors have been studied in the various types of cardiomyopathies. The data indicate associations with the strength of the association varying depending on the kind of neuropeptide and the nature of the cardiomyopathy-diabetic, ischemic, inflammatory, stress-induced or restricitive cardiomyopathy. Several neuropeptides appear to alter regulation of genes involved in heart failure. Demonstration of an association is an essential first step in proving causality or establishing a role for a factor in a disease. Understanding the complexity of neuropeptide function should be helpful in establishing new or optimal therapeutic strategies for the treatment of heart failure in cardiomyopathies.
    Full-text · Article · Aug 2014 · Peptides
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    ABSTRACT: Background Chronic hyperglycemia has been associated with increased oxidative stress in skeletal muscle and sympathetic nerve dysfunction. We investigated the effect of chronic hyperglycemia on the myocardium of patients with uncontrolled diabetes (UD) compared with patients with well-controlled diabetes (CD) and patients without diabetes (ND) after cardioplegic cardiopulmonary bypass (CP/CPB) with acute intraoperative glycemic control. Methods Atrial tissue and serum were collected from 47 patients (ND=18 with glycated hemoglobin [HbA1c] of 5.8 ± 0.2; CD = 8 with HbA1c of 6.1 ± 0.1; with UD = 21 with HbA1c = 9.6 ± 0.5) before and after CP/CPB for immunoblotting, protein oxidation assays, immunohistochemical evaluation, and microarray analysis. Results The uncontrolled group had increased total protein oxidation (p < 0.05) and decreased levels of antioxidative enzyme manganese superoxide dismutase (MnSOD) (p < 0.05) after CP/CPB compared with the controlled group. Collagen staining revealed increased fibrosis in patients with UD (p < 0.05) compared with patients with CD and patients without diabetes. The uncontrolled group also showed a decrease in the neurogenic and angiogenic markers nerve growth factor (NGF) (p < 0.05), neurotrophin (NT)-3 (p < 0.05), and platelet-derived growth factor (PDGF)-β (p < 0.05) compared with the other groups after CP/CPB. Atrial and serum microarray analysis showed increased oxidative stress and sympathetic nerve damage, increased fibrosis, and a decrease in angiogenesis in patients with UD (p < 0.03) compared with patients without diabetes. Conclusions CP/CPB led to higher oxidative stress in patients with UD before surgical intervention, even after normal glucose levels were maintained intraoperatively. Thus, controlled HbA1C in addition to acute intraoperative glucose control may be a more suitable end point for patients with diabetes undergoing cardiac operations.
    No preview · Article · Sep 2014 · The Annals of Thoracic Surgery
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