A novel secreted-cAMP pathway inhibits pulmonary hypertension via a feed-forward mechanism

Abstract

Aims Cyclic adenosine monophosphate (cAMP) is the predominant intracellular second messenger that transduces signals from Gs-coupled receptors. Intriguingly, there is evidence from various cell types that an extracellular cAMP pathway is active in the extracellular space. Herein, we investigated the role of extracellular cAMP in the lung and examined whether it may act on pulmonary vascular cell proliferation and pulmonary vasculature remodelling in the pathogenesis of pulmonary hypertension (PH). Methods and results The expression of cyclic AMP-metabolizing enzymes was increased in lungs from patients with PH as well as in rats treated with monocrotaline and mice exposed to Sugen/hypoxia. We report that inhibition of the endogenous extracellular cAMP pathway exacerbated Sugen/hypoxia-induced lung remodelling. We found that application of extracellular cAMP induced an increase in intracellular cAMP levels and inhibited proliferation and migration of pulmonary vascular cells in vitro. Extracellular cAMP infusion in two in vivo PH models prevented and reversed pulmonary and cardiac remodelling associated with PH. Using protein expression analysis along with luciferase assays, we found that extracellular cAMP acts via the A2R/PKA/CREB/p53/Cyclin D1 pathway. Conclusions Taken together, our data reveal the presence of an extracellular cAMP pathway in pulmonary arteries that attempts to protect the lung during PH, and suggest targeting of the extracellular cAMP signalling pathway to limit pulmonary vascular remodelling and PH.

Therapeutic efficacy of the novel selective RNA polymerase I inhibitor CX‐5461 on pulmonary arterial hypertension and associated vascular remodelling

“…Similar to our observations, these authors demonstrated, in human PASMCs, that nutlin-3 induces cell growth arrest but not apoptosis, whereas whether nutlin-3 has any anti-inflammatory effect in the lungs has not been tested. Studies from other groups have also demonstrated that restoration of p53 functions may underlie the observed therapeutic effects by various interventions in experimental PAH (Abid et al, 2014;Jones et al, 2020). Nevertheless, it should be noted that smooth muscle cells are unlikely to be the only effector cell in vivo which mediate the beneficial effects of CX-5461 and p53 activation.…”

“…In particular, reduced p53 protein in PASMCs may be implicated in the aberrant proliferation of the cells found in PAH (Jones et al, 2020;Wang et al, 2019). Restoration of the normal p53 functions has been linked to therapeutic effects on PAH in animal models (Abid et al, 2014;Jones et al, 2020).…”

“…Mounting evidence from both animal and human studies (including some very recent ones) has demonstrated that the level of p53 protein is decreased in PAH lungs (Abid et al, 2014;Jacquin et al, 2015;Liu et al, 2019;Wakasugi et al, 2019). In particular, reduced p53 protein in PASMCs may be implicated in the aberrant proliferation of the cells found in PAH (Jones et al, 2020;Wang et al, 2019). Restoration of the normal p53 functions has been linked to therapeutic effects on PAH in animal models (Abid et al, 2014;Jones et al, 2020).…”

Zinc-mediated activation of CREB pathway in proliferation of pulmonary artery smooth muscle cells in pulmonary hypertension

“…Moreover, Nox1/Ref-1-mediated activation of CREB promotes gremlin1-driven endothelial cell proliferation and migration in sugen5416 + hypoxia-induced PH model [ 8 ]. However, the role of CREB in pulmonary vascular remodeling remains elusive, because either of the increased and reduced CREB expression has been proposed to mediate PASMCs proliferation in pulmonary vascular remodeling [ 9 – 13 ]. Additionally, the regulatory signaling of CREB activation in PASMCs proliferation has not been well characterized in PH.…”

Molecular and Genetic Profiling for Precision Medicines in Pulmonary Arterial Hypertension

“…Although conventional therapies reduce the symptoms of PAH by leveraging three distinct pathways involved in the vasoconstriction and vasodilation imbalance, none of the approved therapies have shown satisfactory results in reversing PAH. Accumulating clinical evidence suggests that the shortcoming of current treatments may be due to the multifactorial nature of PAH and the genetic variations among patients [ 126 , 127 , 128 , 129 , 130 , 131 ].…”