Gucy1a1-KO Mouse

Gucy1a1 encodes one subunit of the soluble guanylyl cyclase (sGC) protein, a heterodimer formed with the subunit encoded by Gucy1b1. sGC is an effector enzyme of nitric oxide (NO) and is involved in pathways influencing vasoreactivity, platelet function, and blood pressure regulation [1,2,3]. It plays a significant role in cardiovascular-related biological processes and may be associated with diseases such as coronary artery disease [1,2]. Genetic models, like the zebrafish mutant gucy1a1 line generated by CRISPR-Cas9, are valuable for studying its functions [2].

In a zebrafish gucy1a1 mutant line, a 4-bp deletion frameshift mutation reduced gucy1a1 expression. This led to a significant increase in blood flow and linear velocity, with more pronounced effects in homozygotes. Co-morpholino downregulation of gucy1a1 and gucy1b1 also increased blood flow and linear velocity, while individual morpholino downregulation of each gene showed no significant differences. Additionally, the sGC stimulator BAY41-2272 rescued impaired cGMP production in gucy1a1 ± mutant larvae [2]. In Ldlr -/- mice, functional loss of sGC in platelets contributed to atherosclerotic plaque formation, particularly by increasing in vivo leukocyte adhesion to atherosclerotic lesions. Supernatant from activated platelets lacking sGC promoted leukocyte adhesion to endothelial cells by activating them, and reduced platelet angiopoietin-1 release in sGC-depleted platelets enhanced leukocyte adhesion. Pharmacological sGC stimulation increased platelet angiopoietin-1 release in vitro and reduced leukocyte recruitment and atherosclerotic plaque formation [1].

In conclusion, Gucy1a1 is crucial for normal sGC function, which in turn is vital for maintaining proper blood flow, platelet function, and preventing atherosclerotic plaque formation. Studies using gene-modified zebrafish and mouse models have provided valuable insights into its role in these biological processes and associated disease conditions, highlighting its potential as a therapeutic target for cardiovascular diseases.

References:

1. Mauersberger, Carina, Sager, Hendrik B, Wobst, Jana, Schunkert, Heribert, Kessler, Thorsten. 2022. Loss of soluble guanylyl cyclase in platelets contributes to atherosclerotic plaque formation and vascular inflammation. In Nature cardiovascular research, 1, 1174-1186. doi:10.1038/s44161-022-00175-w. https://pubmed.ncbi.nlm.nih.gov/37484062/

2. Vishnolia, Krishan K, Rakovic, Aleksandar, Hoene, Celine, Aherrahrou, Zouhair, Erdmann, Jeanette. 2021. sGC Activity and Regulation of Blood Flow in a Zebrafish Model System. In Frontiers in physiology, 12, 633171. doi:10.3389/fphys.2021.633171. https://pubmed.ncbi.nlm.nih.gov/33716783/

3. Rippe, C, Albinsson, S, Guron, G, Nilsson, H, Swärd, K. 2018. Targeting transcriptional control of soluble guanylyl cyclase via NOTCH for prevention of cardiovascular disease. In Acta physiologica (Oxford, England), 225, e13094. doi:10.1111/apha.13094. https://pubmed.ncbi.nlm.nih.gov/29754438/