Microsomal Prostaglandin E Synthase-1 Expression by Aortic Smooth Muscle Cells Attenuates the Differentiated Phenotype

Abstract

The development of numerous types of cardiovascular disease is associated with alteration of the vascular smooth muscle cell (SMC) phenotype. We have previously shown that abdominal aortic aneurysm progression in a mouse model of the disease is associated with reduced differentiation of SMCs within the lesion and that cyclooxygenase-2 (COX-2) is critical to initiation and progression of the aneurysms. The current studies utilized human aortic SMC (hASMC) cultures to better characterize mechanisms responsible for COX-2-dependent modulation of the SMC phenotype. Depending on the culture conditions, hASMCs expressed multiple characteristics of a differentiated and contractile phenotype, or a de-differentiated and secretory phenotype. The pharmacological inhibition of COX-2 promoted the differentiated phenotype whereas treatment with the COX-2-derived metabolite prostaglandin E2 (PGE2) increased characteristics of the de-differentiated phenotype. Furthermore, pharmacological inhibition or siRNA-mediated knockdown of microsomal prostaglandin E synthase-1 (mPGES-1), the enzyme that functions down-stream of COX-2 during the synthesis of PGE2, significantly increased expression of characteristics of the differentiated SMC phenotype. Therefore, our findings suggest that COX-2 and mPGES-1 -dependent synthesis of PGE2 contributes to a de-differentiated hASMC phenotype and that mPGES-1 may provide a novel pharmacological target for treatment of cardiovascular diseases where altered SMC differentiation has a causative role.

Heme oxygenase-1 mitigates ferroptosis in renal proximal tubule cells

“…Primers (Invitrogen, Grand Island, NY) used were as follows (5=-3=): mouse HO-1 forward 5=-GGTGATGGCTTCCTTGTACC-3= and reverse 5=-AGTGAGGC-CCATACCAGAAG-3=; and GAPDH forward 5=-ATCATCCCTG-CATCCACT-3= and reverse 5=-ATCCACGACGGACACATT-3=. Relative mRNA expression was quantified using the ⌬⌬ Ct method (1,28), and GAPDH was used as an internal control. Results were expressed as fold change over vehicle-treated cells.…”

The Emerging Therapeutic Role of Prostaglandin E2 Signaling in Pulmonary Hypertension

“…Vascular remodeling is seen in large and smaller distal pulmonary arteries. Under physiological conditions, SMCs of normal mature blood vessels exist in a state of contraction, differentiation, and quiescence [34]. The proliferation of SMCs is the main pathological features of vascular remodeling.…”

“…Its hemodynamic characteristics are pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg and PVR > 2 WU [4]. PH can be divided into mild (26)(27)(28)(29)(30)(31)(32)(33)(34)(35), moderate (36)(37)(38)(39)(40)(41)(42)(43)(44)(45), and severe (>45 mmHg) according to the mPAP at rest. The incidence of PH is second only Metabolites 2023, 13, 1152 2 of 15 to coronary heart disease and hypertension among cardiovascular diseases, and it represents a major global health problem due to its high mortality rate [8,9].…”