抄録
Left ventricular (LV) remodeling and hypertrophy is closely associated with the development of congestive heart failure. Obese populations have a high prevalence to promote LV concentric remodeling, however the mechanism remains unexplored. Although prostaglandin E receptor subtype 4 (EP4) affects cardiac function, no available information focuses on its role in LV concentric remodeling. The aim of this study was to investigate the role of EP4 in LV concentric remodeling under high-fat condition.
Six-week old male EP4+/+ and EP4-/- mice was fed with standard chow or high-fat diet (HFD, 20% protein, 60% fat and 20% carbohydrate) for eight weeks. The effects of EP4 deficiency on cardiac function, cardiomyocytes hypertrophy and myocardial fibrosis in mice were studied. The possible regulatory mechanisms were further investigated.
Echocardiography showed that heart from HFD-fed EP4-/- mice had a 54% increase in relative wall thickness and a 38.1% reduction in LV diastolic volumn, but preserved LV mass as compared to that from wild type littermates, suggesting EP4-/- mice were having worse LV concentric remodeling. EP4-/- mice also developed cardiac hypertrophy after HFD feeding, as showed by an increased ratio of heart-to-body weight (by 204.6%), an enlarged cardiomyocyte size (by 170.4%), and elevated mRNA expression of cardiac hypertrophy markers, atrial natriuretic peptide (ANP) (by 68.6%) and brain natriuretic peptide (BNP) (by 241.7%) as compared to wild type mice. Severe myocardial fibrosis was also observed in high-fat treated EP4-/- mice with elevated mRNA level of collagen synthetic genes (collagen I, collagen III, transforming growth factor beta 1) and suppressed degradation of matrix collagen genes (matrix metalloproteinase-2, Decorin). The phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), a protein that promotes concentric remodeling and hypertrophy, was increased in cardiac tissue of high-fat treated EP4-/- mice.
In summary, EP4 deficiency induced LV concentric remodeling, cardiomyocytes hypertrophy and myocardial fibrosis, which may be through activated ERK1/2 signaling. Overall, EP4 plays an essential role in regulation of LV concentric remodeling and myocardial fibrosis under high-fat condition.
