The mechanistic basis of prostacyclin and its stable analogues in pulmonary arterial hypertension: Role of membrane versus nuclear receptors

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• 作者：Lucie H. Clapp ; ^{l.clapp@ucl.ac.uk" class="auth_mail" title="E-mail the corresponding author} ; Rijan Gurung
• 关键词：Cell proliferation ; Pulmonary arterial hypertension ; Vascular remodelling ; Prostanoid receptors ; Peroxisome proliferator-activator receptor ; Prostacyclin analogues ; Cyclic AMP ; Treprostinil ; Iloprost ; Beraprost
• 刊名：Prostaglandins and Other Lipid Mediators
• 出版年：2015
• 出版时间：July 2015
• 年：2015
• 卷：120
• 期：Complete
• 页码：56-71
• 全文大小：2620 K

文摘

Pulmonary arterial hypertension (PAH) is a progressive disease of distal pulmonary arteries in which patients suffer from elevated pulmonary arterial pressure, extensive vascular remodelling and right ventricular failure. To date prostacyclin (PGI₂) therapy remains the most efficacious treatment for PAH and is the only approved monotherapy to have a positive impact on long-term survival. A key thing to note is that improvement exceeds that predicted from vasodilator testing strongly suggesting that additional mechanisms contribute to the therapeutic benefit of prostacyclins in PAH. Given these agents have potent antiproliferative, anti-inflammatory and endothelial regenerating properties suggests therapeutic benefit might result from a slowing, stabilization or even some reversal of vascular remodelling in vivo. This review discusses evidence that the pharmacology of each prostacyclin (IP) receptor agonist so far developed is distinct, with non-IP receptor targets clearly contributing to the therapeutic and side effect profile of PGI₂ (EP₃), iloprost (EP₁), treprostinil (EP₂, DP₁) along with a family of nuclear receptors known as peroxisome proliferator-activated receptors (PPARs), to which PGI₂ and some analogues directly bind. These targets are functionally expressed to varying degrees in arteries, veins, platelets, fibroblasts and inflammatory cells and are likely to be involved in the biological actions of prostacylins. Recently, a highly selective IP agonist, selexipag has been developed for PAH. This agent should prove useful in distinguishing IP from other prostanoid receptors or PPAR binding effects in human tissue. It remains to be determined whether selectivity for the IP receptor gives rise to a superior or inferior clinical benefit in PAH.