Targeting PDE4B (Phosphodiesterase-4 Subtype B) for Cardioprotection in Acute Myocardial Infarction via Neutrophils
Qing Wan1, Chuansheng Xu1, Liyuan Zhu1
1State Key Laboratory of Cardiovascular Disease (Q.W., C.X., L.Z., Y.Z., Z.P., H.C., H.R., F.C., X.N., X.Y., S.H., M.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Insights
Selective inhibition of phosphodiesterase-4 subtype B (PDE4B) reduces myocardial ischemia-reperfusion (MI/R) injury by mitigating neutrophil inflammation and microvascular obstruction. This offers a potential therapeutic strategy for acute myocardial infarction patients undergoing reperfusion therapy.
Area of Science:
- Cardiovascular Biology
- Inflammation and Immunology
- Pharmacology
Background:
- Acute myocardial infarction (MI) treatment involves restoring blood flow, but ischemia-reperfusion (MI/R) injury remains a challenge.
- Phosphodiesterase-4 (PDE4) enzymes, particularly PDE4B, play a role in cellular signaling via cyclic adenosine monophosphate hydrolysis.
Purpose of the Study:
- To investigate the specific role of phosphodiesterase-4 subtype B (PDE4B) in myocardial ischemia-reperfusion (MI/R) injury.
- To explore the therapeutic potential of targeting PDE4B in the context of acute myocardial infarction.
Main Methods:
- Mice underwent 30-minute coronary artery ligation followed by 24-hour reperfusion.
- Cardiac function, perfusion, and vasomotor reactivity were assessed.
- PDE4B expression and localization were analyzed in mouse and human cardiac tissues.
Main Results:
- Cardiac PDE4B expression increased post-reperfusion, localized in endothelial and myeloid cells.
- PDE4B deletion significantly reduced infarct size and improved cardiac function.
- PDE4B mediated neutrophil infiltration, inflammation, and microvascular obstruction.
- PDE4B inhibition improved coronary microcirculation and vasodilation.
Conclusions:
- PDE4B is a critical mediator of neutrophil-driven inflammation and microvascular dysfunction in MI/R injury.
- Targeting PDE4B may offer a protective strategy for patients with acute myocardial infarction undergoing reperfusion.
Background:
Timely and complete restoration of blood flow is the most effective intervention for patients with acute myocardial infarction. However, the efficacy is limited by myocardial ischemia-reperfusion (MI/R) injury. PDE4 (phosphodiesterase-4) hydrolyzes intracellular cyclic adenosine monophosphate and it has 4 subtypes A-D. This study aimed to delineate the role of PDE4B (phosphodiesterase-4 subtype B) in MI/R injury.
Methods:
Mice were subjected to 30-minute coronary artery ligation, followed by 24-hour reperfusion. Cardiac perfusion was assessed by laser Doppler flow. Vasomotor reactivities were determined in mouse and human coronary (micro-)arteries.
Results:
Cardiac expression of PDE4B, but not other PDE4 subtypes, was increased in mice following reperfusion. PDE4B was detected primarily in endothelial and myeloid cells of mouse and human hearts. PDE4B deletion strikingly reduced infarct size and improved cardiac function 24-hour or 28-day after MI/R. PDE4B in bone marrow-derived cells promoted MI/R injury and vascular PDE4B further exaggerated this injury. Mechanistically, PDE4B mediated neutrophil-endothelial cell interaction and PKA (protein kinase A)-dependent expression of cell adhesion molecules, neutrophil cardiac infiltration, and release of proinflammatory cytokines. Meanwhile, PDE4B promoted coronary microcirculatory obstruction and vascular permeability in MI/R, without affecting flow restriction-induced thrombosis. PDE4B blockade increased flow-mediated vasodilatation and promoted endothelium-dependent dilatation of coronary arteries in a PKA- and nitric oxide-dependent manner. Furthermore, postischemia administration with piclamilast, a PDE4 pan-inhibitor, improved cardiac microcirculation, suppressed inflammation, and attenuated MI/R injury in mice. Incubation with sera from patients with acute myocardial infarction impaired acetylcholine-induced relaxations in human coronary microarteries, which was abolished by PDE4 inhibition. Similar protection against MI/R-related coronary injury was recapitulated in mice with PDE4B deletion or inhibition, but not with the pure vasodilator, sodium nitroprusside.
Conclusions:
PDE4B is critically involved in neutrophil inflammation and microvascular obstruction, leading to MI/R injury. Selective inhibition of PDE4B might protect cardiac function in patients with acute myocardial infarction designated for reperfusion therapy.
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