Glypican 1 and syndecan 1 differently regulate noradrenergic hypertension development: Focus on IP3R and calcium

Simone R Potje; Ayman Isbatan; Rita C Tostes; Lusiane M Bendhack; Randal O Dull; Joao L Carvalho-de-Souza; Andreia Z Chignalia

doi:10.1016/j.phrs.2021.105813

Glypican 1 and syndecan 1 differently regulate noradrenergic hypertension development: Focus on IP3R and calcium

Pharmacol Res. 2021 Oct:172:105813. doi: 10.1016/j.phrs.2021.105813. Epub 2021 Aug 16.

Authors

Simone R Potje¹, Ayman Isbatan², Rita C Tostes³, Lusiane M Bendhack⁴, Randal O Dull⁵, Joao L Carvalho-de-Souza⁶, Andreia Z Chignalia⁷

Affiliations

¹ Department of Anesthesiology, College of Medicine Tucson, University of Arizona, USA; Department of Anesthesiology, College of Medicine, University of Illinois at Chicago, USA; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil; Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
² Department of Anesthesiology, College of Medicine, University of Illinois at Chicago, USA.
³ Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
⁴ Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
⁵ Department of Anesthesiology, College of Medicine Tucson, University of Arizona, USA; Department of Physiology, College of Medicine Tucson, University of Arizona, USA; Department of Pathology, College of Medicine Tucson, University of Arizona, USA.
⁶ Department of Anesthesiology, College of Medicine Tucson, University of Arizona, USA; Department of Physiology, College of Medicine Tucson, University of Arizona, USA.
⁷ Department of Anesthesiology, College of Medicine Tucson, University of Arizona, USA; Department of Physiology, College of Medicine Tucson, University of Arizona, USA; Department of Pharmacology and Toxicology, College of Pharmacy Tucson, University of Arizona, USA. Electronic address: azchignalia@email.arizona.edu.

Abstract

Background: Vascular dysfunction is a checkpoint to the development of hypertension. Heparan sulfate proteoglycans (HSPG) participate in nitric oxide (NO) and calcium signaling, key regulators of vascular function. The relationship between HSPG-mediated NO and calcium signaling and vascular dysfunction has not been explored. Likewise, the role of HSPG on the control of systemic blood arterial pressure is unknown. Herein, we sought to determine if the HSPG syndecan 1 and glypican 1 control systemic blood pressure and the progression of hypertension.

Purpose: To determine the mechanisms whereby glypican 1 and syndecan 1 regulate vascular tone and contribute to the development of noradrenergic hypertension.

Experimental approach and key results: By assessing systemic arterial blood pressure we observed that syndecan 1 (Sdc1^-/-) and glypican 1 (Gpc1^-/-) knockout mice show a similar phenotype of decreased systolic blood pressure that is presented in a striking manner in the Gpc1^-/- strain. Gpc1^-/- mice are also uniquely protected from a norepinephrine hypertensive challenge failing to become hypertensive. This phenotype was associated with impaired calcium-dependent vasoconstriction and altered expression of calcium-sensitive proteins including SERCA and calmodulin. In addition, Gpc1^-/- distinctively showed decreased IP₃R activity and increased calcium storage in the endoplasmic reticulum.

Conclusions and implications: Glypican 1 is a trigger for the development of noradrenergic hypertension that acts via IP₃R- and calcium-dependent signaling pathways. Glypican 1 may be a potential target for the development of new therapies for resistant hypertension or conditions where norepinephrine levels are increased.

Keywords: Acetylcholine (Pubmed CID:187); Caffeine (Pubmed CID:2519); Calcium; Calcium dichloride (Pubmed CID: 5284359); Glypican 1; Hypertension; IP(3)R; Nifedipine (Pubmed CID: 4485); Norepinephrine; Norepinephrine bitartrate (Pubmed CID: 297812); Phenylephrine (Pubmed CID: 6041); Potassium Chloride (Pubmed CID: 4873); Sodium Nitroprusside (Pubmed CID: 11953895); Syndecan 1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Aorta, Thoracic / drug effects*
Aorta, Thoracic / metabolism
Aorta, Thoracic / physiology
Blood Pressure / drug effects
Calcium / metabolism*
Glypicans / genetics*
Hypertension* / genetics
Hypertension* / metabolism
Inositol 1,4,5-Trisphosphate Receptors / metabolism*
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Norepinephrine / pharmacology*
Syndecan-1 / genetics*

Substances

Glypicans
Inositol 1,4,5-Trisphosphate Receptors
Syndecan-1
Calcium
Norepinephrine

Grants and funding

850700/AHA/American Heart Association-American Stroke Association/United States