Early Cellular Changes in the Ascending Aorta and Myocardium in a Swine Model of Metabolic Syndrome

Rabya Saraf,Frank Sellke,Feroze Mahmood,David Liu,Amit Bardia,Thomas Huang,Khurram Owais,Venkatachalam Senthilnathan,Antonio D Lassaletta,Kamal R Khabbaz,Robina Matyal

doi:10.1371/journal.pone.0146481

Rabya Saraf, Frank Sellke + Show 9 more

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https://doi.org/10.1371/journal.pone.0146481

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Abstract

BackgroundMetabolic syndrome is associated with pathological remodeling of the heart and adjacent vessels. The early biochemical and cellular changes underlying the vascular damage are not fully understood. In this study, we sought to establish the nature, extent, and initial timeline of cytochemical derangements underlying reduced ventriculo-arterial compliance in a swine model of metabolic syndrome.MethodsYorkshire swine (n = 8 per group) were fed a normal diet (ND) or a high-cholesterol (HCD) for 12 weeks. Myocardial function and blood flow was assessed before harvesting the heart. Immuno-blotting and immuno-histochemical staining were used to assess the cellular changes in the myocardium, ascending aorta and left anterior descending artery (LAD).ResultsThere was significant increase in body mass index, blood glucose and mean arterial pressures (p = 0.002, p = 0.001 and p = 0.024 respectively) in HCD group. At the cellular level there was significant increase in anti-apoptotic factors p-Akt (p = 0.007 and p = 0.002) and Bcl-xL (p = 0.05 and p = 0.01) in the HCD aorta and myocardium, respectively. Pro-fibrotic markers TGF-β (p = 0.01), pSmad1/5 (p = 0.03) and MMP-9 (p = 0.005) were significantly increased in the HCD aorta. The levels of pro-apoptotic p38MAPK, Apaf-1 and cleaved Caspase3 were significantly increased in aorta of HCD (p = 0.03, p = 0.04 and p = 0.007 respectively). Similar changes in coronary arteries were not observed in either group. Functionally, the high cholesterol diet resulted in significant increase in ventricular end systolic pressure and–dp/dt (p = 0.05 and p = 0.007 respectively) in the HCD group.ConclusionPreclinical metabolic syndrome initiates pro-apoptosis and pro-fibrosis pathways in the heart and ascending aorta, while sparing coronary arteries at this early stage of dietary modification.

Highlights

Metabolic syndrome is defined as the cohort of risk factors that increase the likelihood of developing cardiovascular disease and type II diabetes mellitus [1]
The levels of pro-apoptotic p38 mitogen-activated protein kinases (p38MAPK), Apaf-1 and cleaved Caspase3 were significantly increased in aorta of high-cholesterol diet (HCD) (p = 0.03, p = 0.04 and p = 0.007 respectively)
There was no significant difference in the body mass index (BMI) between the groups at the beginning of the experiment (25.8 ± 6 kg/m3 vs. 27.3 ± 3 kg/m3, p = 0.4)

Summary

Introduction

Metabolic syndrome is defined as the cohort of risk factors that increase the likelihood of developing cardiovascular disease (such as coronary artery disease) and type II diabetes mellitus [1] These physiologic and biochemical changes include abdominal obesity, raised blood pressure, pro-thrombotic state, pro-inflammatory state, insulin resistance, hypertension, and atherogenic dyslipidemia [1]. Simultaneous vascular involvement results in local inflammation, endothelial damage, and atherosclerosis, which cause large artery stiffness, decreased compliance, and coronary artery flow problems [4,5,6]. While clinically, they are within the spectrum of presentation of metabolic syndrome, the similarity at the biochemical and cellular level has not been conclusively established yet. We sought to establish the nature, extent, and initial timeline of cytochemical derangements underlying reduced ventriculo-arterial compliance in a swine model of metabolic syndrome.

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