The Balance Between Prostaglandin E2 Ep3 And Ep4 Receptors Determines Severity Of Cardiac Damage In Myocardial Infarction And An Angiotensin Ii-Induced Model Of Hypertension
According to the center for disease control about 610,000 people die every year in the United States from heart disease, of which, coronary heart disease is the most common form. One major risk factor for heart attack is hypertension, which affects nearly half of all Americans [472, 473]. PGE2 plays an important role in regulating cardiovascular function and mediating inflammation, both of which contribute to the development of hypertension and/or heart disease. Prostaglandin E2 can act as a vasodilator or vasoconstrictor depending on which of its receptor subtypes are activated.
In general, activation of the EP1 and EP3 receptors is vasoconstrictive while EP2/EP4 activation promotes vasodilation . Treatment with an EP4 agonist has been shown to protect the heart during reperfusion after ischemia, while antagonizing EP4 reduced cardiac function and exacerbated cardiac remodeling [267, 394]. We have published that mice lacking the EP4 receptor in cardiomyocytes develop heart failure and have worsened cardiac function after MI [73, 268]. With regard to the EP3 receptor, we have published that its activation reduces contractility in isolated cardiomyocyte preparations and in the ex-vivo Langedorff system .
In this dissertation, we have been the first to show in both the MI and the Ang II hypertension model, that EP3 expression increases significantly, whereby the expression of EP4 does not change or increases slightly. Thus, we hypothesize that the deleterious effects of PGE2 are via the EP3 receptor. Furthermore, we have presented here that overexpression of the EP4 receptor in the cardiomyocytes is protective in a mouse model of MI by improving cardiac function, and reducing fibrosis and inflammation . We postulated that the mechanism of reduced inflammation may be mediated by the cardiac fibroblasts. We therefore show in isolated adult mouse cardiac fibroblasts, that PGE2 and an EP4 receptor agonist reduce LPS-stimulated MCP-5 production. Lastly, we report that activation of the EP3 receptor is deleterious in Ang II hypertension and that systemic administration of an EP3 antagonist can reduce blood pressure after Ang II infusion.