Molecular Mechanisms Regulating the Vascular Prostacyclin Pathways and Their Adaptation during Pregnancy and in the Newborn

Majed, Batoule H.; Khalil, Raouf A.

doi:10.1124/pr.111.004770

Cited by 209 publications

(161 citation statements)

References 293 publications

(470 reference statements)

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“…A Golgi cPLA 2␣ /COX-2/mPGES-1 System for PGE 2 Synthesis-Reddy and Herschman (54) were the first to demonstrate that when COX-1 and COX-2 are co-expressed in cells that COX-2 can function with endogenously mobilized AA, whereas COX-1 is effectively latent; however, when treated with a bolus of exogenous AA, both COX-1 and COX-2 are operative. Several explanations have been proffered for these observations.…”

Section: Journal Of Biological Chemistrymentioning

confidence: 99%

“…Furthermore, we found that mPGES-1 is also located in the Golgi apparatus. Finally, another key enzyme, cPLA 2 , which plays a central role in regulating AA release for PGE 2 synthesis in response to intracellular Ca 2ϩ mobilization, binds to Golgi in preference to ER membranes at lower cytosolic Ca 2ϩ concentrations (46). According to our model (Fig.…”

mentioning

confidence: 91%

“…immunity (1), reproduction (2), and renal and cardiovascular homeostasis (3,4). Two isoforms, prostaglandin-H synthases-1 and -2, catalyze the committed step in the biosynthesis of PGs from arachidonic acid (AA).…”

mentioning

confidence: 99%

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A Cyclooxygenase-2-dependent Prostaglandin E2 Biosynthetic System in the Golgi Apparatus

Yuan

Smith

2015

Journal of Biological Chemistry

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Background: When cyclooxygenases-1 and -2 (COXs-1 and -2) are co-expressed, COX-2 can function, whereas COX-1 is latent. Results: Significant amounts of COX-2, microsomal PGE synthase-1, and cytosolic PLA 2␣ but not COX-1 are in the Golgi. Conclusion: Cytosolic PLA 2␣ , COX-2, and microsomal PGE synthase-1 comprise a unique COX-2-dependent PGE 2 biosynthetic system in the Golgi. Significance: COX-2 and COX-1 can function in different subcellular compartments.

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Section: Journal Of Biological Chemistrymentioning

confidence: 99%

mentioning

confidence: 91%

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A Cyclooxygenase-2-dependent Prostaglandin E2 Biosynthetic System in the Golgi Apparatus

Yuan

Smith

2015

Journal of Biological Chemistry

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“…Prostaglandin E 2 (PGE 2 ) controls vascular tone, inflammation, and vascular wall remodeling through activation of prosatglandin E2 receptor 1-4 (EP1-4) receptor subtypes (Majed and Khalil, 2012). PGE 2 stimulation of EP2/EP4 receptors causes MMP activation in human endometriotic epithelial and stromal cells (Lee et al, 2011).…”

Section: Other Potential Mmp Activators In Vvsmentioning

confidence: 99%

Matrix Metalloproteinases as Regulators of Vein Structure and Function: Implications in Chronic Venous Disease

MacColl

Khalil

2015

J Pharmacol Exp Ther

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Lower-extremity veins have efficient wall structure and function and competent valves that permit upward movement of deoxygenated blood toward the heart against hydrostatic venous pressure. Matrix metalloproteinases (MMPs) play an important role in maintaining vein wall structure and function. MMPs are zinc-binding endopeptidases secreted as inactive pro-MMPs by fibroblasts, vascular smooth muscle (VSM), and leukocytes. ProMMPs are activated by various activators including other MMPs and proteinases. MMPs cause degradation of extracellular matrix (ECM) proteins such as collagen and elastin, and could have additional effects on the endothelium, as well as VSM cell migration, proliferation, Ca 21 signaling, and contraction. Increased lower-extremity hydrostatic venous pressure is thought to induce hypoxia-inducible factors and other MMP inducers/ activators such as extracellular matrix metalloproteinase inducer, prostanoids, chymase, and hormones, leading to increased MMP expression/activity, ECM degradation, VSM relaxation, and venous dilation. Leukocyte infiltration and inflammation of the vein wall cause further increases in MMPs, vein wall dilation, valve degradation, and different clinical stages of chronic venous disease (CVD), including varicose veins (VVs). VVs are characterized by ECM imbalance, incompetent valves, venous reflux, wall dilation, and tortuosity. VVs often show increased MMP levels, but may show no change or decreased levels, depending on the VV region (atrophic regions with little ECM versus hypertrophic regions with abundant ECM) and MMP form (inactive pro-MMP versus active MMP). Management of VVs includes compression stockings, venotonics, and surgical obliteration or removal. Because these approaches do not treat the causes of VVs, alternative methods are being developed. In addition to endogenous tissue inhibitors of MMPs, synthetic MMP inhibitors have been developed, and their effects in the treatment of VVs need to be examined.

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“…12,13,20 Finally, phospholipase A2 (PLA2) which plays an important enzymatic role in prostaglandin formation may be upregulated in concert with the increased prostaglandin activity seen in ductal smooth muscle cells during ductal transition. 28 An ultimate goal of our group is to develop gene-based approaches to treat symptomatic PDA that fail medical therapy. The success of any type of gene therapy relies first and foremost on safety of the approach.…”

Section: Discussionmentioning

confidence: 99%

Identification of differentially regulated genes in human patent ductus arteriosus

Parikh

Bai

Swartz

et al. 2016

Exp Biol Med (Maywood)

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In order to identify differentially expressed genes that are specific to the ductus arteriosus, 18 candidate genes were evaluated in matched ductus arteriosus and aortic samples from infants with coarctation of the aorta. The cell specificity of the gene's promoters was assessed by performing transient transfection studies in primary cells derived from several patients. Segments of ductus arteriosus and aorta were isolated from infants requiring repair for coarctation of the aorta and used for mRNA quantitation and culturing of cells. Differences in expression were determined by quantitative PCR using the ÁÁCt method. Promoter regions of six of these genes were cloned into luciferase reporter plasmids for transient transfection studies in matched human ductus arteriosus and aorta cells. Transcription factor AP-2b and phospholipase A2 were significantly up-regulated in ductus arteriosus compared to aorta in whole tissues and cultured cells, respectively. In transient transfection experiments, Angiotensin II type 1 receptor and Prostaglandin E receptor 4 promoters consistently gave higher expression in matched ductus arteriosus versus aorta cells from multiple patients. Taken together, these results demonstrate that several genes are differentially expressed in ductus arteriosus and that their promoters may be used to drive ductus arteriosus-enriched transgene expression.

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Molecular Mechanisms Regulating the Vascular Prostacyclin Pathways and Their Adaptation during Pregnancy and in the Newborn

Cited by 209 publications

References 293 publications

A Cyclooxygenase-2-dependent Prostaglandin E2 Biosynthetic System in the Golgi Apparatus

A Cyclooxygenase-2-dependent Prostaglandin E2 Biosynthetic System in the Golgi Apparatus

Matrix Metalloproteinases as Regulators of Vein Structure and Function: Implications in Chronic Venous Disease

Identification of differentially regulated genes in human patent ductus arteriosus

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