Prostacyclin (PGI₂) is a vasodilator and platelet inhibitor, properties consistent with cardioprotection. More than a decade ago, inhibition of cyclooxygenase-2 (COX-2) by the nonsteroidal anti-inflammatory drugs (NSAIDs) rofecoxib and celecoxib was found to reduce the amount of the major metabolite of PGI₂ (PGI-M) in the urine of healthy volunteers. This suggested that NSAIDs might cause adverse cardiovascular events by reducing production of cardioprotective PGI₂. This prediction was based on the assumption that the concentration of PGI-M in urine likely reflected vascular production of PGI₂ and that other cardioprotective mediators, especially nitric oxide (NO), were not able to compensate for the loss of PGI₂. Subsequently, eight placebo-controlled clinical trials showed that NSAIDs that block COX-2 increase adverse cardiovascular events. We connect tissue-specific effects of NSAID action and functional correlates in mice with clinical outcomes in humans by showing that deletion of COX-2 in the mouse vasculature reduces excretion of PGI-M in urine and predisposes the animals to both hypertension and thrombosis. Furthermore, vascular disruption of COX-2 depressed expression of endothelial NO synthase and the consequent release and function of NO. Thus, suppression of PGI₂ formation resulting from deletion of vascular COX-2 is sufficient to explain the cardiovascular hazard from NSAIDs, which is likely to be augmented by secondary mechanisms such as suppression of NO production.

Inadequate vitamin D status has been linked to increased risk of type 2 diabetes and cardiovascular disease. Inducible cyclooxygenase (COX) isoform COX-2 has been involved in the pathogenesis of such chronic inflammatory diseases. We found that the active form of vitamin D, 1,25(OH)₂D produces dose-dependent inhibition of COX-2 expression in murine macrophages under both basal and LPS-stimulated conditions and suppresses proinflammatory mediators induced by LPS. Administration of 1,25(OH)₂D significantly alleviated local inflammation in a carrageenan-induced paw edema mouse model. Strikingly, the phosphorylation of both Akt and its downstream target IκBα in macrophages were markedly suppressed by 1,25(OH)₂D in the presence and absence of LPS stimulation through up-regulation of THEM4 (thioesterase superfamily member 4), an Akt modulator protein. Knockdown of both vitamin D receptor and THEM4 attenuated the inhibitory effect of 1,25(OH)₂D on COX-2 expression in macrophages. A functional vitamin D-responsive element in the THEM4 promoter was identified by chromatin immunoprecipitation and luciferase reporter assay. Our results indicate that vitamin D restrains macrophage-mediated inflammatory processes by suppressing the Akt/NF-κB/COX-2 pathway, suggesting that vitamin D supplementation might be utilized for adjunctive therapy for inflammatory disease.

Chemotherapeutic agents, such as doxorubicin (DOX), may cause cardiomyopathy, even life-threatening arrhythmias in cancer patients. Ferroptosis-an iron-dependent oxidative form of programmed necrosis, plays a pivotal role in DOX-induced cardiomyopathy (DIC). Prostaglandins (PGs) are bioactive signaling molecules that profoundly modulate cardiac performance in both physiologic and pathologic conditions. Here, we found that PGE₂ production and its E-prostanoid 1 receptor (EP1) expression were upregulated in erastin (a ferroptosis inducer) or DOX-treated cardiomyocytes. EP1 inhibition markedly aggravated erastin or DOX-induced cardiomyocyte ferroptosis, whereas EP1 activation exerted opposite effect. Genetic depletion of EP1 in cardiomyocytes worsens DOX-induced cardiac injury in mice, which was efficiently rescued by the ferroptosis inhibitor Ferrostatin-1 (Fer-1). Mechanistically, EP1 activation protected cardiomyocytes from DOX-induced ferroptosis by promoting nuclear factor erythroid 2-related factor 2 (Nrf2)-driven anti-oxidative gene expression, such as glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). EP1 was coupled with G_αq to elicit intracellular Ca²⁺ flux and activate the PKC/Nrf2 cascade in ferroptotic cardiomyocytes. EP1 activation also prevents DOX-induced ferroptosis in human cardiomyocytes. Thus, PGE₂/EP1 axis protects cardiomyocytes from DOX-induced ferroptosis by activating PKC/Nrf2 signaling and activation of EP1 may represent an attractive strategy for DIC prevention and treatment.

Niacin, as an antidyslipidemic drug, elicits a strong flushing response by release of prostaglandin (PG) D₂. However, whether niacin is beneficial for inflammatory bowel disease (IBD) remains unclear. Here, we observed niacin administration‐enhanced PGD₂ production in colon tissues in dextran sulfate sodium (DSS)‐challenged mice, and protected mice against DSS or 2,4,6‐trinitrobenzene sulfonic acid (TNBS)‐induced colitis in D prostanoid receptor 1 (DP1)‐dependent manner. Specific ablation of DP1 receptor in vascular endothelial cells, colonic epithelium, and myeloid cells augmented DSS/TNBS‐induced colitis in mice through increasing vascular permeability, promoting apoptosis of epithelial cells, and stimulating pro‐inflammatory cytokine secretion of macrophages, respectively. Niacin treatment improved vascular permeability, reduced apoptotic epithelial cells, promoted epithelial cell update, and suppressed pro‐inflammatory gene expression of macrophages. Moreover, treatment with niacin‐containing retention enema effectively promoted UC clinical remission and mucosal healing in patients with moderately active disease. Therefore, niacin displayed multiple beneficial effects on DSS/TNBS‐induced colitis in mice by activation of PGD₂/DP1 axis. The potential efficacy of niacin in management of IBD warrants further investigation. Synopsis Niacin, an ancient lipid‐lowering drug that elicits a strong flushing response through release of prostaglandin (PG) D₂. Niacin improves experimentally induced ulcerative colitis in mice and humans through the activation of PGD₂/DP1 axis. Niacin increases PGD₂ release in both mice and humans. Niacin confers protection against DSS/TNBS‐induced colitis in mice through DP1‐mediated inhibition of vascular leakage, suppression of colonic epithelium apoptosis, and reduction of pro‐inflammatory cytokine secretion. Retention enema treatment containing niacin effectively promotes clinical remission and mucosal healing in patients with moderately active UC.

Pulmonary arterial hypertension (PAH) is commonly associated with chronic hypoxemia in disorders such as chronic obstructive pulmonary disease (COPD). Prostacyclin analogs are widely used in the management of PAH patients; however, clinical efficacy and long-term tolerability of some prostacyclin analogs may be compromised by concomitant activation of the E-prostanoid 3 (EP3) receptor. Here, we found that EP3 expression is upregulated in pulmonary arterial smooth muscle cells (PASMCs) and human distal pulmonary arteries (PAs) in response to hypoxia. Either pharmacological inhibition of EP3 or Ep3 deletion attenuated both hypoxia and monocrotaline-induced pulmonary hypertension and restrained extracellular matrix accumulation in PAs in rodent models. In a murine PAH model, Ep3 deletion in SMCs, but not endothelial cells, retarded PA medial thickness. Knockdown of EP3α and EP3β, but not EP3γ, isoforms diminished hypoxia-induced TGF-β1 activation. Expression of either EP3α or EP3β in EP3-deficient PASMCs restored TGF-β1 activation in response to hypoxia. EP3α/β activation in PASMCs increased RhoA-dependent membrane type 1 extracellular matrix metalloproteinase (MMP) translocation to the cell surface, subsequently activating pro–MMP-2 and promoting TGF-β1 signaling. Activation or disruption of EP3 did not influence PASMC proliferation. Together, our results indicate that EP3 activation facilitates hypoxia-induced vascular remodeling and pulmonary hypertension in mice and suggest EP3 inhibition as a potential therapeutic strategy for pulmonary hypertension.

Apoptotic death of cardiac myocytes is associated with ischemic heart disease and chemotherapy‐induced cardiomyopathy. Chemoattractant receptor‐homologous molecule expressed on T helper type 2 cells (CRTH2) is highly expressed in the heart. However, its specific role in ischemic cardiomyopathy is not fully understood. Here, we demonstrated that CRTH2 disruption markedly improved cardiac recovery in mice postmyocardial infarction and doxorubicin challenge by suppressing cardiomyocyte apoptosis. Mechanistically, CRTH2 activation specifically facilitated endoplasmic reticulum (ER) stress‐induced cardiomyocyte apoptosis via caspase‐12‐dependent pathway. Blockage of m‐calpain prevented CRTH2‐mediated cardiomyocyte apoptosis under ER stress by suppressing caspase‐12 activity. CRTH2 was coupled with G_αq to elicit intracellular Ca²⁺ flux and activated m‐calpain/caspase‐12 cascade in cardiomyocytes. Knockdown of caspase‐4, an alternative to caspase‐12 in humans, markedly alleviated CRHT2 activation‐induced apoptosis in human cardiomyocyte response to anoxia. Our findings revealed an unexpected role of CRTH2 in promoting ER stress‐induced cardiomyocyte apoptosis, suggesting that CRTH2 inhibition has therapeutic potential for ischemic cardiomyopathy. Synopsis Chemoattractant receptor‐homologous molecule expressed on T‐helper type‐2 cells (CRTH2), which mediates the chemoattractant effect of prostaglandin (PG) D2 in leukocytes, is shown here to promote ER stress‐induced cardiomyocyte apoptosis through caspase‐12‐dependent pathway. PGD2/CRTH2 signaling in cardiomyocytes is activated upon ER stress such as anoxia and doxorubicin (DOX) challenge. CRTH2 promotes ER stress‐induced apoptosis in cardiomyocytes through Gαq/m‐calpain/caspase‐12 signaling pathway. CRTH2 inhibition confers cardioprotection against myocardial infaction or DOX treatment in mice by reducing cardiomyocyte apoptosis.