Similar dysfunctional Ca²⁺ regulation in coronary smooth muscle from explanted human hearts and Ossabaw miniature swine strongly supports the translational relevance of this large animal model

Abstract

IntroductionEstablishing a suitable animal model for metabolic syndrome (MetS) and coronary artery disease (CAD) is a challenge, as there are numerous risk factors and uncontrollable variables in the human population. However, Ossabaw miniature swine have been used with great success to recapitulate MetS and CAD in. The goal of this study was to determine whether the Ossabaw miniature swine is a clinically relevant large animal model on the cellular level, specifically with regards to intracellular Ca2+ ([Ca2+]i) handling, which is crucial for coronary smooth muscle (CSM) function.MethodsExplanted human hearts from 32 heart failure patients (22 male, 10 female; aged 53.4 ± 2.1 years) undergoing transplantation surgery at the Methodist Hospital in Indianapolis, IN were collected. Coronary arteries were excised and CSM cells were enzymatically dispersed and loaded with the fluorescent [Ca2+]i indicator fura‐2. [Ca2+]i levels were measured during depolarization‐induced Ca2+ influx and caffeine‐induced sarcoplasmic reticulum (SR) Ca2+ store release.ResultsIn explanted human hearts exhibiting either ischemic or dilated non‐ischemic cardiomyopathy, a greater coronary artery neointima formation was inversely correlated to depolarization‐induced Ca2+ influx and SR Ca2+ release in CSM cells. Furthermore, a greater number of MetS risk factors, including some factors individually (body mass index, LDL/HDL cholesterol ratio) was also correlated to decreased Ca2+ entry and, in patients with ischemic cardiomyopathy, decreased SR Ca2+ store release. Increased age, however, was correlated to an increased SR Ca2+ store release. These data are all consistent with previous studies of Ossabaw swine CSM.ConclusionThe similar CSM Ca2+ regulation in coronary arteries of humans and Ossabaw swine provides strong evidence for the phenomenal translational relevance of this large animal model, both on the whole‐animal level and the CSM [Ca2+]i signaling level.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.