Prostaglandin D2 signaling and cardiovascular homeostasis

doi:10.1016/j.yjmcc.2022.03.011

Journal of Molecular and Cellular Cardiology

Volume 167, June 2022, Pages 97-105

https://doi.org/10.1016/j.yjmcc.2022.03.011 Get rights and content

Highlights

•
Dysregulation of PGD₂ mediated signaling is involved in the pathogenesis of CVDs.
•
DP1 activation elicits CVDs protection through promoting inflammation resolution.
•
ER-anchored CRTH2 suppresses injury-induced organ fibrosis.
•
Niacin exerts beneficial effects on CVDs partially by activation of PGD₂/DP1 axis.

Abstract

Cardiovascular diseases are the leading cause of death worldwide. A chronic inflammatory response is a common pathological alteration in diverse cardiovascular diseases. Prostaglandin (PG) D₂, a key lipid mediator derived from arachidonic acid metabolism, promotes resolution of inflammation and regulated T cell function through its receptors. Accumulated evidence has shown that dysregulated PGD₂ signaling is involved in the pathogenesis of cardiovascular diseases, including atherosclerosis, hypertension, pulmonary hypertension, abdominal aortic aneurysm, and myocardial ischemia. Here, we summarized the recent progresses on PGD₂ in cardiovascular homeostasis and discussed potential therapeutic translation by targeting PGD₂ signaling.

Introduction

Cardiovascular diseases (CVDs) are the leading cause of mortality and disability globally. There are many risk factors of developing CVDs, such as age, sex, familial inheritance, hyperlipidemia, diabetes, obesity, smoking, unhealthy diet, sedentary lifestyle and work stress. In various CVDs, immune cells are activated, and they infiltrate affected tissues. For instance, multiple types of inflammatory cells are found in atherosclerotic plaques [1], ischemic hearts [2], and kidneys in patients with hypertension [3]. Prostanoids-a class of bioactive inflammatory mediators, including prostaglandin (PG) E₂, PGD₂, PGI₂, PGF_2α, and thromboxane A₂ (TxA₂), derived from arachidonic acid by the sequential action of cyclooxygenases (COXs), and PG synthase(s) are involved in the pathogenesis of inflammation and multiple CVDs [4]. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to relieve pain and suppress fever and inflammation by inhibiting COX activity. PGE₂ is a typical pro-inflammatory mediator, also displays anti-inflammatory property which is context dependent [5,6]. PGI₂ and TxA₂ exert opposite effects on vascular tone and platelet activation [7]. PGF_2α promotes systemic inflammation and vascular injury [8,9]. PGD₂ is recognized as a pro-resolution mediator in inflamed tissues [[10], [11], [12]]. It has been implicated in the regulation of sleep [13], reproduction [14] and progression of allergic inflammation-related diseases [[15], [16], [17]]. Emerging studies have demonstrated that PGD₂ plays an important role in the regulation of cardiovascular homeostasis and blood pressure (BP) [6]. In this review, we summarized the function and underlying mechanisms of the pro-resolving PGD₂-mediated signaling in the development of CVDs (atherosclerosis, BP regulation, pulmonary vascular remodeling, abdominal aortic aneurysm, and myocardial injury) and highlighted PGD₂ receptors as potential therapeutic targets for the management of CVDs.

Section snippets

PGD₂ biosynthesis and its receptors

PGD₂ is formed through multi-enzymatic cascade reactions, including oxygenation of arachidonic acid to PGH₂ by COXs and the isomerization of PGH₂ to PGD₂ by PGD synthases (PGDSs). There are two distinct PGD₂ synthases: lipocalin-type PGDS (L-PGDS) and hematopoietic PGDS (H-PGDS). L-PGDS is unique in its bifunctional character as a catalytic enzyme that synthesizes PGD₂ and as a secretary protein of the lipocalin superfamily that carries small lipophilic molecules such as retinol [18] and

PGD₂ signaling and atherosclerosis

Atherosclerosis is a complex chronic inflammatory disease within the arterial wall that is initiated by endothelial cell dysfunction in response to increased levels of oxidized low-density lipoproteins (LDLs). Dysfunction of endothelial cells promotes attraction, attachment, and rolling of circulating monocytes, which subsequently take up oxidized LDLs, transform into foam cells, and form typical atherosclerotic plaques [42]. Vascular smooth muscle cells (VSMCs) migrate into the intima of the

PGD₂ and BP regulation

PGs are involved in the regulation of fluid/electrolyte balance and the renin-angiotensin-aldosterone system [61,62]. Almost all NSAIDs cause systemic or salt-sensitive hypertension [62,63]. Interestingly, COX-1-and COX-2-derived PGs have opposite renal effects [64]. In rodents, COX-1 deletion or inhibition represses angiotensin II (AngII)-induced hypertensive response, whereas COX-2 deletion or inhibition reduces renal medulla blood flow and enhances AngII-induced hypertensive response [64]. A

PGD₂ signaling and pulmonary vascular remodeling

Pulmonary vascular remodeling is the pathological hallmark of pulmonary arterial hypertension (PAH) and involves alterations in the intima, media, and adventitia [75]. COX-2 deficiency exacerbates hypoxia-induced PAH in mice by increasing VSMC contractility [76], indicating that its downstream PG products are involved in PAH development. PGI₂ analogs (beraprost, iloprost, and treprostinil) and PGI₂ receptor agonists are widely used in clinical settings to manage PAH by relaxing human pulmonary

PGD₂ and abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA), a chronic vascular degenerative disease, is characterized by the apoptosis of SMCs and degeneration of the aortic media [105]. Chronic inflammation is a central player in the pathogenesis of AAA [106]; different subsets of inflammatory cells infiltrate the media and adventitia of AAA, including monocytes/macrophages, T and B lymphocytes, and dendritic cells. H-PGDS-derived PGD₂ and its metabolite, 15d-PGJ₂, promote the resolution of inflammation by regulating

PGD₂ and myocardial injury

Ischemia (such as coronary thrombosis) and chemotherapeutic drugs (such as doxorubicin [DOX]) often cause myocardial injury. Inflammatory reactions and massive PGs are induced in the heart tissues after ischemic conditions [12,107] or DOX treatment [108]. Treatment with COX-2 inhibitors improved the left ventricular function and reduced mortality in a DOX-induced heart failure murine model [109]. In contrast, deletions of both COX-1 and COX-2 exaggerate ischemia or DOX-induced cardiac injury in

Pharmacology of PGD₂ signaling modulation

PGD₂ exerts both pro-inflammatory and anti-inflammatory effects in different disease states: it promotes allergic airway inflammation and mediates the resolution of non-allergic inflammation. Accumulating evidence has shown that PGD₂ has beneficial effects on various CVDs, such as ischemic heart disease, atherosclerosis, and hypertension, probably through the activation of downstream DP1. Niacin, an old medicine with broad-spectrum lipid-lowering properties, can markedly increase PGD₂

Conclusions and perspectives

In summary, PGD₂, as a vasodilator and pro-resolution mediator, plays an important role in the regulation of cardiovascular homeostasis. Activation of the PGD₂/DP1 axis elicits cardiovascular protection against hypoxia-induced pulmonary vascular remodeling, aging-related hypertension, atherosclerosis, abdominal aortic aneurysm, and ischemic cardiac injury through the inhibition of macrophages and T cell-mediated inflammatory response, and pulmonary VSMC proliferation and hypertrophy (Fig. 1).

Disclosures

None.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (81790623, 82030015, 82170253), grants from Science and Technology Commission of Shanghai Municipality, China (21QA1407400, 21ZR1481200). Ying Yu is a fellow at the Jiangsu Collaborative Innovation Center for Cardiovascular Disease Translational Medicine.

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Prostaglandin (PG) D₂, a commonly considered vasodilator through D prostanoid receptor-1 (DP1), might also evoke vasoconstriction via acting on the thromboxane (Tx)-prostanoid receptor (the original receptor of TxA₂; TP) and/or E prostanoid receptor-3 (one of the vasoconstrictor receptors of PGE₂; EP3). This study aimed to test the above hypothesis in the mouse renal vascular bed (main renal arteries and perfused kidneys) and/or mesenteric resistance arteries and determine how the vasoconstrictor mechanism influences the overall PGD₂ effect on systemic blood pressure under in vivo conditions. Experiments were performed on control wild-type (WT) mice and mice with deficiencies in TP (TP^−/−) and/or EP3 (EP3^−/−). Here we show that PGD₂ indeed evoked vasoconstrictor responses in the above-mentioned tissues of WT mice, which were however not only reduced by TP^−/− or EP3^−/−, but also reversed by TP^−/−/EP3^−/− in some of the above tissues (mesenteric resistance arteries or perfused kidneys) to dilator reactions that were reduced by non-selective DP antagonism. A slight or mild pressor response was also observed with PGD₂ under in vivo conditions, and this was again reversed to a depressor response in TP^−/− or TP^−/−/EP3^−/− mice. Non-selective DP antagonism reduced the PGD₂-evoked depressor response in TP^−/−/EP3^−/− mice as well. These results thus demonstrate that like other PGs, PGD₂ activates TP and/or EP3 to evoke vasoconstrictor activities, which can outweigh its concurrent vasodepressor activity mediated mainly through DP1, and hence result in a pressor response, although the response might only be of a slight or mild extent.
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Review articleProstaglandin D2 signaling and cardiovascular homeostasis

Highlights

Abstract

Introduction

Section snippets

PGD2 biosynthesis and its receptors

PGD2 signaling and atherosclerosis

PGD2 and BP regulation

PGD2 signaling and pulmonary vascular remodeling

PGD2 and abdominal aortic aneurysm

PGD2 and myocardial injury

Pharmacology of PGD2 signaling modulation

Conclusions and perspectives

Disclosures

Acknowledgments

J. Lipid Res.

Biochim. Biophys. Acta

Front. Pharmacol.

Biochim. Biophys. Acta

Vitam. Horm.

Neurosci. Lett.

J. Biol. Chem.

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Trends Mol. Med.

Eur. J. Pharmacol.

J. Biol. Chem.

Atherosclerosis

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Prostaglandins Other Lipid Mediat

Immunity

Ageing Res. Rev.

Ageing Res. Rev.

Biochem. Biophys. Res. Commun.

J. Am. Coll. Cardiol.

Biochem. Pharmacol.

Pharmacol. Ther.

Biochem. Pharmacol.

Am. J. Hypertens.

Clin. Ther.

Atherosclerosis

Chest

Macrophages and T cells in atherosclerosis: a translational perspective

Am. J. Physiol. Heart Circ. Physiol.

Activated T lymphocytes are essential drivers of pathological remodeling in ischemic heart failure

Circ. Heart Fail.

Role of T-cell activation in salt-sensitive hypertension

Am. J. Physiol. Heart Circ. Physiol.

Prostaglandins and inflammation

Arterioscler. Thromb. Vasc. Biol.

The key contribution of platelet and vascular arachidonic acid metabolism to the pathophysiology of atherothrombosis

Cardiovasc. Res.

Prostaglandin F2alpha receptor antagonist attenuates LPS-induced systemic inflammatory response in mice

FASEB J.

Inducible cyclooxygenase may have anti-inflammatory properties

Nat. Med.

Hematopoietic prostaglandin D2 synthase controls the onset and resolution of acute inflammation through PGD2 and 15-deoxyDelta12 14 PGJ2

Proc. Natl. Acad. Sci. U. S. A.

PKA regulatory IIalpha subunit is essential for PGD2-mediated resolution of inflammation

J. Exp. Med.

Prostaglandin D2 and reproduction

Am. J. Reprod. Immunol.

Activator protein-1 mediates shear stress-induced prostaglandin d synthase gene expression in vascular endothelial cells

Arterioscler. Thromb. Vasc. Biol.

Therapeutic potential of hematopoietic prostaglandin D2 synthase in allergic inflammation

Cells

Antagonism of the prostaglandin D2 receptors DP1 and CRTH2 as an approach to treat allergic diseases

Nat. Rev. Drug Discov.

Lipocalin-type prostaglandin D synthase/beta-trace is a major amyloid beta-chaperone in human cerebrospinal fluid

Proc. Natl. Acad. Sci. U. S. A.

Expression and purification of cysteine mutation isoforms of rat lipocalin-type prostaglandin D synthase for nuclear magnetic resonance study

Acta Biochim. Biophys. Sin. Shanghai

Expression of lipocalin-type prostaglandin D synthase (beta-trace) in human heart and its accumulation in the coronary circulation of angina patients

Proc. Natl. Acad. Sci. U. S. A.

The major source of endogenous prostaglandin D2 production is likely antigen-presenting cells. Localization of glutathione-requiring prostaglandin D synthetase in histiocytes, dendritic, and Kupffer cells in various rat tissues

J. Immunol.

Review article
Prostaglandin D₂ signaling and cardiovascular homeostasis

PGD₂ biosynthesis and its receptors

PGD₂ signaling and atherosclerosis

PGD₂ and BP regulation

PGD₂ signaling and pulmonary vascular remodeling

PGD₂ and abdominal aortic aneurysm

PGD₂ and myocardial injury

Pharmacology of PGD₂ signaling modulation