Determination of the role of prostaglandins in inflammatory diseases with cardiovascular comorbidities, new treatment opportunities and clinical implications

Prostaglandin (PG) E2 is formed from arachidonic acid by the enzymatic actions of either cyclooxygenase (COX)-1 or COX-2 into PGH2, which is further metabolized by microsomal prostaglandin E synthase-1 (mPGES-1) into PGE2. mPGES-1 has emerged as a cardiovascular safe anti-inflammatory drug target.

Our characterizations of inhibitors of mPGES-1 demonstrate their potent anti-inflammatory actions while causing relaxation of arteries. mPGES-1 inhibition also significantly protects heart functions following myocardial infarction in vivo.

The underlying mechanisms include inhibition of PGE2 biosynthesis, an increase of local prostacyclin formation, no effects on the ADMA-NO pathway and an unbroken formation of anti-inflammatory PGD2/15-deoxy-PGJ2 ( a cyclopentenone).

These compounds are considered anti-inflammatory and antiviral and recognized as a part of the family “specialized pro-resolving lipid mediators”. We have identified MGST3 as the key enzyme conjugating cyclopentenone with glutathione. Inhibition of MGST3 leads to increased 15-deoxy-PGJ2 levels with lesser amounts of PGE2.

We aim to characterize MGST3 as a novel modulator of inflammation. Furthermore, we will investigate prostaglandins and other lipids as biomarkers for rheumatoid arthritis.

We will also characterize our findings demonstrating activation of the thromboxane A2 pathway and platelet activation as a likely mechanism of action for the severe cardiovascular side effects observed for JAK inhibitors.