- Intimal hyperplasia characterized by abnormal accumulation of smooth muscle cell (SMC)-like cells and inflammatory cells is a hallmark of vascular occlusive disorders such as post angioplasty restenosis, vein graft atherosclerosis, and allograft vasculopathy. The current therapies with drug-eluting stents to inhibit SMC proliferation and induce SMC death still have problems due to limited endothelial cell regrowth and increased risk of thrombosis. Moreover, drug-eluting stents effective for focal lesions are not appropriate for diffuse atherosclerotic disease. Thus, there is high demand to develop novel therapeutic strategies. Our unbiased genome-wide genetic polymorphism association study in mice has identified cyclic nucleotide phosphodiesterase 10A (PDE10A, catalyzing cyclic nucleotide hydrolysis) as a potential candidate gene contributing to injury-induced intimal hyperplasia. Indeed, PDE10A expression is markedly elevated in the intimal SMC-like cells and macrophages in mouse models of vascular injury and in human atherosclerotic lesions. Our preliminary data with PDE10A knockout mice and PDE10 inhibitor suggest that PDE10A is important in pathological vascular remodeling in vivo. In cultured SMCs, PDE10A depletion or inhibition increases myocardin protein (a master driver of SMC contractile phenotype) and expression of several SMC contractile marker genes. In macrophages, we found that PDE10A is important for NLRP3 inflammasome expression and activation. PDE10A expression is up-regulated by growth factors and inflammatory cytokines. Bioinformatic analysis identified a highly conserved intronic putative transcriptional regulatory sequence at the single-nucleotide polymorphism (SNP) site identified by our mouse genetic association study, and it may be responsible for regulating PDE10A gene expression during phenotype switching and stimulation of inflammation. Thus, we hypothesize that increased PDE10A expression, by inhibiting cAMP signaling, promotes synthetic SMC phenotype transition and macrophage inflammasome expression/activation; and thus stimulates intimal hyperplasia. The overall objective of this proposal is to investigate the mechanisms that regulate expression of PDE10A, and PDE10A's specific role in the processes responsible for intimal hyperplasia. To achieve our goals, two Specific Aims are proposed: (1) Determine the role of PDE10A in intimal formation and vascular remodeling after injury using both genetic and pharmacological approaches. (2) Define the mechanisms for PDE10A regulation of vascular pathology: regulation of PDE10A expression, transition of SMC phenotype, and stimulation of vascular inflammation. PDE10A is well known in psychosis; and PDE10A inhibitor has been developed for clinical trials to treat schizophrenia. However, PDE10A regulation and function in cardiovascular system remains largely unknown. Our studies should yield novel therapeutic strategies to limit pathologic intimal hyperplasia given PDE10A has proved to be a druggable target.
- RELEVANCE TO PUBLIC HEALTH Pathological vascular remodeling characterized by abnormal cell growth, inflammatory cell accumulation, and extracellular matrix deposition is a hallmark of vascular occlusive disorders such as atherosclerosis, postangioplasty restenosis, vein graft stenosis, and allograft vasculopathy. The proposed study will explore the role, therapeutic potential, and the mechanism of action of PDE10A isoform in diverse vascular disease models and human saphenous vein explants discarded from cardiac bypass surgeries. The PDE10A specific inhibitor is developed and in clinical trial for treating schizophrenia. Thus our findings may identify PDE10A as a novel therapeutic target for treating occlusive vascular diseases.
| Zhang, Yi-Shuai; Li, Jian-Dong; Yan, Chen (2018) An update on vinpocetine: New discoveries and clinical implications. Eur J Pharmacol 819:30-34 |
| Zhang, Yishuai; Knight, Walter; Chen, Si et al. (2018) Multiprotein Complex With TRPC (Transient Receptor Potential-Canonical) Channel, PDE1C (Phosphodiesterase 1C), and A2R (Adenosine A2 Receptor) Plays a Critical Role in Regulating Cardiomyocyte cAMP and Survival. Circulation 138:1988-2002 |
| Chen, Si; Knight, Walter E; Yan, Chen (2018) Roles of PDE1 in Pathological Cardiac Remodeling and Dysfunction. J Cardiovasc Dev Dis 5: |
| Korshunov, Vyacheslav A; Wang, Hexuan; Ahmed, Rifat et al. (2017) Model-based vascular elastography improves the detection of flow-induced carotid artery remodeling in mice. Sci Rep 7:12081 |
