PDE5A, a cGMP-specific phosphodiesterase, hydrolyzes cGMP to GMP. It is involved in multiple physiological and pathological pathways, including those related to vascular tone regulation, neuronal signaling, and skeletal remodeling [3,6,7,8]. In vascular smooth muscle cells, it plays a key role in regulating vascular tone, and in skeletal tissue, it may be involved in the NO-cGMP-PKG pathway important for skeletal homeostasis [6,8].

In the context of pulmonary arterial hypertension (PAH), miR-30d can attenuate PAH and pulmonary vascular remodeling by targeting PDE5A. In miR-30d knockout rats treated with sildenafil (a PDE5A inhibitor), suppressing miR-30d partially weakens the beneficial effect of sildenafil against monocrotaline-induced pulmonary hypertension and vascular remodeling, indicating that PDE5A is a crucial target in PAH treatment [1]. In bipolar disorder, single-nucleus RNA sequencing of human basal ganglia shows upregulation of PDE5A in caudate medium spiny neurons. Overexpression of PDE5A in mouse striatum leads to decreased cGMP level, increased neuroinflammation gene expression, and bipolar-like behaviors, suggesting its causative role in bipolar disorder [2]. In thyroid cancer, lncRNA ARAP1-AS1 promotes cancer progression through the miR-516b-5p/PDE5A axis, highlighting PDE5A's role in cancer development [4]. Also, PDE5A polymorphisms influence the response to sildenafil treatment in patients with erectile dysfunction, with the rs3806808 polymorphism's G-allele carriers showing a worse response, especially in non-diabetic patients [5].

In summary, PDE5A is involved in diverse biological functions and is associated with multiple diseases such as PAH, bipolar disorder, thyroid cancer, and erectile dysfunction. Studies using knockout or transgenic models, like miR-30d transgenic and knockout rats in PAH research, and overexpression models in bipolar disorder research, have revealed its role in these disease conditions, providing insights for potential therapeutic strategies.

References:

1. Liang, Xuchun, Zhou, Jingwen, Wang, Hongyun, Xiao, Junjie, Bei, Yihua. 2024. miR-30d Attenuates Pulmonary Arterial Hypertension via Targeting MTDH and PDE5A and Modulates the Beneficial Effect of Sildenafil. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2407712. doi:10.1002/advs.202407712. https://pubmed.ncbi.nlm.nih.gov/39206778/

2. Bai, Zhixin, Li, Peilong, Gao, Xu, Zhu, Ying, You, Linya. 2024. Exploring PDE5A upregulation in bipolar disorder: insights from single-nucleus RNA sequencing of human basal ganglia. In Translational psychiatry, 14, 494. doi:10.1038/s41398-024-03202-5. https://pubmed.ncbi.nlm.nih.gov/39695100/

3. Shaik, Althaf, Agarwal, Harshit K, Bhakuni, Rashmi, Kirubakaran, Sivapriya. . Novel Pyrazolo[4, 3-c]Quinolin-3-One Derivatives as PDE5A Inhibitors. In Current topics in medicinal chemistry, 19, 305-315. doi:10.2174/1568026619666190208164402. https://pubmed.ncbi.nlm.nih.gov/30747070/

4. Du, Qiuli, Huang, Lin, Guo, Wei. 2022. LncRNA ARAP1-AS1 targets miR-516b-5p/PDE5A axis to facilitate the progression of thyroid cancer. In Anti-cancer drugs, 34, 735-746. doi:10.1097/CAD.0000000000001438. https://pubmed.ncbi.nlm.nih.gov/36730555/

5. Marchal-Escalona, Cristobal, Herrera-Imbroda, Bernardo, Clemente-Postigo, Mercedes, Lara, María Fernanda, Cardona, Fernando. 2016. PDE5A Polymorphisms Influence on Sildenafil Treatment Success. In The journal of sexual medicine, 13, 1104-10. doi:10.1016/j.jsxm.2016.04.075. https://pubmed.ncbi.nlm.nih.gov/27235284/

6. Gebska, Milena A, Stevenson, Blake K, Hemnes, Anna R, Berkowitz, Dan E, Champion, Hunter C. 2011. Phosphodiesterase-5A (PDE5A) is localized to the endothelial caveolae and modulates NOS3 activity. In Cardiovascular research, 90, 353-63. doi:10.1093/cvr/cvq410. https://pubmed.ncbi.nlm.nih.gov/21421555/

7. Carøe Nordgaard, Julie, Kruse, Lars Schack, Gammeltoft, Steen, Kruuse, Christina Rostrup. 2014. Role of Ser102 and Ser104 as regulators of cGMP hydrolysis by PDE5A. In PloS one, 9, e107627. doi:10.1371/journal.pone.0107627. https://pubmed.ncbi.nlm.nih.gov/25247292/

8. Kim, Se-Min, Yuen, Tony, Iqbal, Jameel, Rubin, Mishaela R, Zaidi, Mone. 2020. The NO-cGMP-PKG pathway in skeletal remodeling. In Annals of the New York Academy of Sciences, 1487, 21-30. doi:10.1111/nyas.14486. https://pubmed.ncbi.nlm.nih.gov/32860248/