Alternative splicing impairs soluble guanylyl cyclase function in aortic aneurysm
Open accessAbstract
Nitric oxide (NO) receptor soluble guanylyl cyclase (sGC) is a key regulator of several important vascular functions and is important for maintaining cardiovascular homeostasis and vascular plasticity. Diminished sGC expression and function contributes to pathogenesis of several cardiovascular diseases. However, the processes that control sGC expression in vascular tissue remain poorly understood. Previous work in animal and cell models revealed the complexity of alternative splicing of sGC genes and demonstrated its importance in modulation of sGC function. The aim of this study was to examine the role of alternative splicing of α1 and β1 sGC in healthy and diseased human vascular tissue. Our study found a variety of α1 and β1 sGC splice forms expressed in human aorta. Their composition and abundance were different between samples of aortic tissue removed during surgical repair of aortic aneurysm and samples of aortas without aneurysm. Aortas with aneurysm demonstrated decreased sGC activity, which correlated with increased expression of dysfunctional sGC splice variants. In addition, the expression of 55-kDa oxidation-resistant α1 isoform B sGC (α1-IsoB) was significantly lower in aortic samples with aneurysm. The α1-IsoB splice variant was demonstrated to support sGC activity in aortic lysates. Together, our results suggest that alternative splicing contributes to diminished sGC function in vascular dysfunction. Precise understanding of sGC splicing regulation could help to design new therapeutic interventions and to personalize sGC-targeting therapies in treatments of vascular disease.
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The sGC heme group shows high selectivity toward NO, can bind CO weakly, but shows no affinity toward molecular oxygen.
“Remarkably, unlike most other hemoproteins that bind oxygen, CO and NO, this heme group shows a high selectivity toward NO and can also bind CO weakly but shows no affinity toward molecular oxygen (625).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [625]
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- Authors
- Martin, E., Golunski, E., Laing, S. T., Estrera, A. L., & Sharina, I. G.
- Affiliations
- The University of Texas Health Science Center at Houston (US)
- Corresponding author
- Sharina, Iraida G.
- Venue
- American Journal of Physiology-Heart and Circulatory Physiology
- Publisher
- American Physiological Society
- Published
- 2014-12-01
- Volume
- 307
- Issue
- 11
- Pages
- H1565-H1575
- ISSN
- 0363-6135 (ISSN-L)
- 1522-1539
- PMC
- PMC4255009
- OpenAlex
- W2110760839
- Cited by
- 23
- References
- 52
- Citations by year
- 2026: 1 · 2024: 3 · 2023: 2 · 2022: 3 · 2021: 4 · 2018: 2 · 2017: 2 · 2016: 3 · 2015: 2 · 2014: 1
- FWCI
- 1.77
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Heart and Circulatory Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL088128)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Aortic Disease and Treatment Approaches
- Keywords
- alternative splicing, soluble guanylate cyclase, aortic aneurysm, nitric oxide signaling, vascular dysfunction, aorta
- MeSH terms
- Soluble Guanylyl Cyclase, Adult, Aged, Aged, 80 and over, Animals, Aortic Aneurysm, Cloning, Molecular, Female, Genotype, Cyclic GMP, Guanylate Cyclase, Humans, Male, Middle Aged, Nitric Oxide, Signal Transduction, Alternative Splicing, Receptors, Cytoplasmic and Nuclear, COS Cells, Young Adult, Precision Medicine
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