Local infiltration of neuropeptide Y as a potential therapeutic agent against apoptosis and fibrosis in a swine model of hypercholesterolemia and chronic myocardial ischemia.
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 5 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 5 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 result in improved myocardial diastolic function. NPY may have a potential therapeutic role in patients with hypercholesterolemia associated coronary artery disease.
Beth Israel Deaconess Medical Center, Department of Anesthesia and Critical Care, CC-454, 1 Deaconess Road, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA. Electronic address: rmatyal@bidmc.harvard.edu.
Robina
R
Matyal
Sruthi
S
Sakamuri
Angela
A
Wang
Eitezaz
E
Mahmood
Michael P
MP
Robich
Kamal
K
Khabbaz
Philip E
PE
Hess
Frank W
FW
Sellke
Feroze
F
Mahmood
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002908:Chronic Disease; D017023:Coronary Angiography; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D006984:Hypertrophy / Q000188:drug therapy; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009478:Neuropeptide Y / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects; D013552:Swine
D005227:Fatty Acids; D051275:Glucose Transporter Type 4; D009478:Neuropeptide Y
Chronic ischemia; Fibrosis; Neuropeptide Y; Oxidative stress