Abstract 4365167: Dampening inflammation by disrupting PDE4B attenuates coronary atherogenesis preventing heart failure

Abstract

Background: Despite historical success of launching cholesterol-lowering drugs, coronary atherosclerotic disease (CAD) remains a leading cause of mortality and morbidity worldwide. The landmark CANTOS trial testifies anti-inflammation (blocking IL-1β) as a promising approach to further curtail CAD. However, its clinical translation halted due to safety concern. Clinical use of phosphodiesterase-4 (PDE4) drug that non-distinguishingly inhibits all four PDE4 subtypes A-D is associated with a decreased risk of cardiovascular disease. This study aimed to delineate the role of PDE4B in coronary atherosclerosis. Methods: Human coronary artery expression of PDE4B was analyzed using specimens from clinically classified CAD patients. Coronary atherosclerosis was induced in a novel mouse model ( ApoE SA/SA ) by hypercholesterolemia and hypertension ( Circ Res . 2025, in press). Pharmacological and genetic interventions were employed to assess the impact of PDE4B disruption on coronary atherosclerosis. Results: PDE4B expression was upregulated during human coronary atherogenesis. Cardiac expression of PDE4B, but not other PDE4 subtypes, was increased in advanced atherosclerotic lesions of mice. PDE4B deficiency attenuated coronary atherosclerosis and reduced cardiovascular death, preventing heart failure in ApoE SA/SA mice. Morphometrics of coronary atherosclerotic plaques revealed that PDE4B deletion reduced neutrophil infiltration and increased endothelial integrity, with less lesional platelets. A gene set enrichment analysis showed that PDE4B promoted leucocyte recruitment and inflammatory response in late atherogenesis. Mechanistically, PDE4B mediated neutrophil extracellular traps (NETs) formation, driving thromboinflammation and endothelial erosion in coronary lesions. PDE4B blockade suppressed release of proinflammatory cytokines, including IL-1β. Consistently, PDE4B deletion mitigated photochemically induced carotid artery thrombosis in the context of atherogenesis. Furthermore, administration with rolipram, a PDE4 pan-inhibitor, significantly retarded coronary atherogenesis in mice, coinciding with suppressed systemic inflammation and improved heart function. Conclusions: PDE4B is critically involved in neutrophil-driven inflammation and promotes coronary atherothrombosis. Selective inhibition of PDE4B bears a promise for CAD treatment and prevention. Keywords: phosphodiesterase-4B; coronary atherosclerosis; vascular inflammation; endothelial erosion; neutrophil