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Abstract 534: Alternative Splicing of Nitric Oxide Receptor Soluble Guanylyl Cyclase in Diseased Human Aortas

Soluble guanylyl cyclase (sGC) is a key enzyme in the NO/cGMP signaling pathway. sGC plays an important role in cardiovascular homeostasis and its activity is crucial for maintaining vascular plasticity. Diminished sGC expression and activity leads to endothelial dysfunction and increase in vascular stiffness. We have previously demonstrated that alternative splicing of sGC genes produces different sGC splice forms with altered enzymatic and regulatory properties. Thus, we examined the expression of alternatively spliced transcripts in human aortic tissue. We also compared levels of expression of different splice forms for α1 and β1 sGC in normal and diseased human aortic samples. De-identified specimens of aortas (full thickness) were collected from patients with descending thoracic, thoracoabdominal and ascending aortic aneurysms (N=12), and compared with aortic samples from cardiovascular healthy donors (N=10). The expression of different α1 and β1 sGC splice variants was assessed by semi-quantitative RT-PCR analysis. Previously, we have characterized functional properties of splice isoform encoded by α1 Transcript 5 and demonstrated that this splice form is resistant to oxidative protein degradation. By estimating the ratio of α1 sGC canonical transcript and α1 Transcript 5, we demonstrated that the relative expression of Transcript 5 splice isoform is increased in diseased in comparison to normal samples (0.54±0.12 AU in normal vs 0.29±0.2 AU in diseased, p=0.0015). We also found that the expression of α1 Transcripts 3 and 6 is increased, while the expression of β1 sGC splice forms β1Δ68Ω43, β1Δ68 and β1Ω2 is decreased in diseased human aortas. Using cGMP immunoassay we assessed NO-dependent cGMP accumulation in aortic tissue and demonstrated that sGC activity varies in different samples correlating with relative expression of individual sGC transcripts. Our data demonstrate for the first time that α1 and β1 sGC undergo alternative splicing in human aortic tissue and that the diversity and abundance of splice isoforms is different in normal and diseased aortas. Our results suggest that splicing is one of the mechanisms regulating sGC expression in aorta in diseased condition.