title: Alternative splicing impairs soluble guanylyl cyclase function in aortic aneurysm.
abstract: 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.
authors.affiliation: Department of Internal Medicine/Cardiology, The University of Texas Health Science Center in Houston Medical School, Houston, Texas; and.
authors.forename: Emil
authors.initials: E
authors.lastname: Martin
authors.affiliation: Department of Internal Medicine/Cardiology, The University of Texas Health Science Center in Houston Medical School, Houston, Texas; and.
authors.forename: Eva
authors.initials: E
authors.lastname: Golunski
authors.affiliation: Department of Internal Medicine/Cardiology, The University of Texas Health Science Center in Houston Medical School, Houston, Texas; and.
authors.forename: Susan T
authors.initials: ST
authors.lastname: Laing
authors.affiliation: Department of Cardiothoracic Vascular Surgery, The University of Texas Health Science Center in Houston Medical School, Houston, Texas.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Estrera
authors.affiliation: Department of Internal Medicine/Cardiology, The University of Texas Health Science Center in Houston Medical School, Houston, Texas; and Iraida.G.Sharina@uth.tmc.edu.
authors.forename: Iraida G
authors.initials: IG
authors.lastname: Sharina
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D001014:Aortic Aneurysm / Q000201:enzymology* / Q000235:genetics*; D019556:COS Cells; D003001:Cloning, Molecular; D006152:Cyclic GMP / Q000502:physiology; D005260:Female; D005838:Genotype; D006162:Guanylate Cyclase / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000502:physiology; D057285:Precision Medicine; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D000071756:Soluble Guanylyl Cyclase; D055815:Young Adult
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP
keywords: alternative splicing; aorta; nitric oxide; soluble guanylyl cyclase