Overexpression of prostaglandin E2 EP4 receptor improves cardiac function after myocardial infarction.
Bryson TD, Gu X, Zhu L, Xu J, Peterson E, Yang XP, and Harding P. Overexpression of prostaglandin E2 EP4 receptor improves cardiac function after myocardial infarction. FASEB Journal 2017; 31(1).
Prostaglandin E2 (PGE2) signals through 4 separate G-protein coupled receptor sub-types (EP1, EP2, EP3 and EP4) to elicit a variety of physiologic and pathophysiological effects. Our laboratory has studied the role of PGE2 via its EP4 receptor and reported that the EP4 receptor causes hypertrophy of cardiac myocytes in vitro; that cardiac myocyte deletion of the EP4 receptor (EP4 KO) worsens cardiac function after MI and that male EP4 KO mice develop dilated cardiomyopathy with age. Moreover, we recently reported that PGE2 via its EP3 receptor could reduce cardiac contractility of isolated myocytes and the working heart preparation. We thus hypothesized that there is an imbalance in the EP3/EP4 ratio towards EP3 in the failing heart and that overexpression of EP4 in a mouse model of heart failure would improve cardiac function. This was tested in a mouse model of myocardial infarction (MI) with the use of AAV9-EP4 driven by the myosin heavy chain promoter to overexpress EP4. Briefly, MI was produced in 10-12 week old C57/Bl6 male mice by ligation of the left anterior descending coronary artery and mice received either 1×1012 viral particles of AAV9-EP4 or the same dose of AAV9-luciferase (AAV9-luc) into the left ventricle (LV) free wall at the time of surgery. Sham-operated mice also received viral injections. At 2 week post-surgery, echocardiography was performed and hearts were harvested for measurement of myocyte cross-sectional area (MCSA), interstitial collagen fraction (ICF) and immunohistochemistry for macrophage infiltration. We found that overexpression of EP4 improved shortening fraction after MI (40.3 ± 2.5 vs 28.2 ± 2.9%, p< 0.005) and ejection fraction (47.7 ± 2.4 vs 37.8 ± 2.2%, p< 0.05) with a reduction in left ventricular dimension at systole (2.13 ± 0.16 vs 2.98 ± 0.26 mm, p < 0.01). As expected, MCSA was increased after MI from 202.4 ± 18.5 μm2 to 296.6 ± 6.0 μm2 (p = 0.005) and this increase was attenuated by administration of AAV9-EP4 to 259.4 ± 4.0 μm2 (p <0.01). Similar changes were also observed in ICF. ICF was increased from 4.86 ± 0.14% in sham operated mice to 7.93 ± 0.53% in MI mice receiving AAV9-luc (p < 0.01) and was reduced in mice receiving AAV9-EP4 to 5.71 ± 0.26% (p = 0.005). In contrast, overexpression of EP4 did not affect the same parameters in sham-operated control mice. As expected, macrophage migration was increased in the LV of mice subject to MI (74.7 ± 5.4 cells/mm2 for sham operated mice vs 283.5 ± 15.1 for MI mice receiving AAV9-luc) and this was reduced to 122.2 ± 5.9 cells/mm2 for MI mice receiving AAV9-EP4 (p < 0.0001 vs MI-luc group). In conclusion, our results support an anti-inflammatory role for PGE2 via EP4 in the myocardium and suggest that overexpression of the EP4 receptor protects against the decline in cardiac function post MI. Thus, the EP4 receptor may be a potential therapeutic target.