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AT(1)-receptor response to non-saturating Ang-II concentrations is amplified by calcium channel blockers
KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0003-0374-4411
Institute of Chemical Biology and Fundamental Medicine, 630090 Novosibirsk,.
KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska Institutet, Sverige.ORCID iD: 0000-0003-0578-4003
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2017 (English)In: BMC Cardiovascular Disorders, ISSN 1471-2261, E-ISSN 1471-2261, Vol. 17, no 1, 126Article in journal (Refereed) Published
Abstract [en]

Background: Blockers of angiotensin II type 1   receptor (AT 1 R) and the voltage gated calcium channel 1.2 (Ca V 1.2) are commonly used for treatment of hypertension. Yet there is little information about the effect of physiological concentrations of angiotensin II (AngII) on AT 1 R signaling and whether there is a reciprocal regulation of AT 1 R signaling by Ca V 1.2.

Methods: To elucidate these questions, we have studied the Ca 2+  signaling response to physiological and pharmacological AngII doses in HEK293a cells, vascular smooth muscle cells and cardiomyocytes using a Ca 2+ sensitive dye as the principal sensor. Intra-cellular calcium recordings were performed in presence and absence of Ca V 1.2 blockers.  Semi- quantitative imaging methods were used to assess the plasma membrane expression of AT 1 R and G-protein activation.

Results: Repeated exposure to pharmacological (100 nM) concentrations of AngII caused, as expected, a down-regulation of the Ca 2+  response. In contrast, repeated exposure to physiological (1 nM) AngII concentration resulted in an enhancement of the Ca 2+  response. The up-regulation of the Ca 2+  response to repeated 1 nM AngII doses and the down- egulation of the Ca 2+  response to repeated 100 nM Angll doses were not accompanied by a parallel change of the AT 1 R plasma membrane expression. The Ca 2+  response to 1 nM of AngII was amplified in the presence of therapeutic concentrations of the Ca V 1.2 blockers, nifedipine and verapamil, in vascular smooth muscle cells, cardiomyocytes and HEK293a cells. Amplification of the AT 1 R response was also observed following inhibition of the calcium permeable transient receptor potential cation channels, suggesting that the activity of AT 1 R is sensitive to calcium influx.

Conclusions: Our findings have implications for the understanding of hyperactivity of the angiotensin system and for use of Ca 2+  channel blockers as mono-therapy in hypertension. 

Place, publisher, year, edition, pages
Stockholm: BioMed Central, 2017. Vol. 17, no 1, 126
Keyword [en]
Calcium, AT1R, Cell imaging, VGCC, hypertension
National Category
Medical and Health Sciences
Research subject
Medical Technology
Identifiers
URN: urn:nbn:se:kth:diva-203989DOI: 10.1186/s12872-017-0562-xISI: 000401701400001PubMedID: 28514967Scopus ID: 2-s2.0-85019540748OAI: oai:DiVA.org:kth-203989DiVA: diva2:1083618
Funder
Swedish Heart Lung FoundationSwedish Research CouncilMagnus Bergvall FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20170328

Available from: 2017-03-21 Created: 2017-03-21 Last updated: 2017-06-13Bibliographically approved
In thesis
1. Studies on molecular mechanisms in calcium signaling and cellular energy consumption
Open this publication in new window or tab >>Studies on molecular mechanisms in calcium signaling and cellular energy consumption
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Ion signaling plays fundamental role in cell survival. Na+ and Ca2+ are critical players in ion signaling. Cells spend the major amount of energy to maintain and regulate Na+ and Ca2+ gradients across the cell membrane. Any disruption in cellular energy consumption by plasma membrane ATPases affects ion signaling and vice versa. This thesis is a combination of four separate research studies. In the first study, We measured ATP consumption dynamics of Na+/K+-ATPase using a genetically encoded fluorescent indicator called Perceval HR. we demonstrate that PercevalHR is an excellent tool to visualize ATP:ADP in mammalian cells.

In the second study, We studied the role of calcium signaling and TRP channels in angiotensin II type 1 receptor  signaling cascade. We prove that low inhibition of CaV1.2 with physiological and therapeutically relevant concentration of Angiotensin II up regulate AT1R signaling.

In the third study, We studied the role of the TRPM5 channel in regulating insulin secretion, and cytoplasmic free calcium concentration in the rat β-cells by usingtriphenyl phosphine oxide, a selective inhibitor of the channel.

In the fourth study, We tested whether, the genetically engineered human β-cell line (EndoC-BH1) could be used as models for studying Ca2+signaling in the context of Type II Diabetes. We found that the EndoC-BH1 cells could be a relevant model to study stimulus-secretion coupling and Ca2+ signaling in the human β-cells.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2017. 76 p.
Keyword
ca2+ signaling, ATP, PercevalHR, NKA, diabetes, Angiotensin
National Category
Medical and Health Sciences
Research subject
Biological Physics
Identifiers
urn:nbn:se:kth:diva-204418 (URN)978-91-7729-337-8 (ISBN)
Public defence
2017-04-19, Fire, Scilifelab, Tomtebodavägen 23a, Solna, 09:00 (English)
Opponent
Supervisors
Note

QC 20170328

Available from: 2017-03-28 Created: 2017-03-27 Last updated: 2017-03-28Bibliographically approved

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