Functionally Selective AT(1) Receptor Activation Reduces Ischemia Reperfusion Injury

Anders Hostrup; Gitte Lund Christensen; Bo Hjort Bentzen; Bo Liang; Mark Aplin; Morten Grunnet; Jakob Lerche Hansen; Thomas Jespersen

doi:10.1159/000341445

Functionally Selective AT(1) Receptor Activation Reduces Ischemia Reperfusion Injury

Anders Hostrup, Gitte Lund Christensen, Bo Hjort Bentzen, Bo Liang, Mark Aplin, Morten Grunnet, Jakob Lerche Hansen, Thomas Jespersen

13 Citations (Scopus)

Abstract

Angiotensin II (AngII) is a key peptide in cardiovascular homeostasis and is a ligand for the Angiotensin II type 1 and 2 seven transmembrane receptors (AT ₁ R and AT ₂ R). The AT ₁ receptor is a seven-transmembrane (7TM) G protein-coupled receptor (GPCR) mediating the majority of the physiological functions of AngII. The AT ₁ R mediates its effects through both G protein-dependent and independent signaling, which can be separated by functionally selective agonists. In the present study we investigate the effect of AngII and the β-arrestin biased agonist [SII]AngII on ischemia-reperfusion injury in rat hearts. Isolated hearts mounted in a Langendorff perfused rat heart preparations showed that preconditioning with [SII]AngII reduced the infarct size induced by global ischemia from 46±8.4% to 22±3.4%. In contrast, neither preconditioning with AngII nor postconditioning with AngII or [SII]AngII had a protective effect. Together these results demonstrate a cardioprotective effect of simultaneous blockade of G protein signaling and activation of G protein independent signaling through AT ₁ receptors.

Original language	English
Journal	Cellular Physiology and Biochemistry
Volume	30
Issue number	3
Pages (from-to)	642-652
Number of pages	11
ISSN	1015-8987
DOIs	https://doi.org/10.1159/000341445
Publication status	Published - Aug 2012

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title = "Functionally Selective AT(1) Receptor Activation Reduces Ischemia Reperfusion Injury",

abstract = " Angiotensin II (AngII) is a key peptide in cardiovascular homeostasis and is a ligand for the Angiotensin II type 1 and 2 seven transmembrane receptors (AT 1 R and AT 2 R). The AT 1 receptor is a seven-transmembrane (7TM) G protein-coupled receptor (GPCR) mediating the majority of the physiological functions of AngII. The AT 1 R mediates its effects through both G protein-dependent and independent signaling, which can be separated by functionally selective agonists. In the present study we investigate the effect of AngII and the β-arrestin biased agonist [SII]AngII on ischemia-reperfusion injury in rat hearts. Isolated hearts mounted in a Langendorff perfused rat heart preparations showed that preconditioning with [SII]AngII reduced the infarct size induced by global ischemia from 46±8.4% to 22±3.4%. In contrast, neither preconditioning with AngII nor postconditioning with AngII or [SII]AngII had a protective effect. Together these results demonstrate a cardioprotective effect of simultaneous blockade of G protein signaling and activation of G protein independent signaling through AT 1 receptors.",

author = "Anders Hostrup and Christensen, {Gitte Lund} and Bentzen, {Bo Hjort} and Bo Liang and Mark Aplin and Morten Grunnet and Hansen, {Jakob Lerche} and Thomas Jespersen",

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year = "2012",

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doi = "10.1159/000341445",

language = "English",

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T1 - Functionally Selective AT(1) Receptor Activation Reduces Ischemia Reperfusion Injury

AU - Hostrup, Anders

AU - Christensen, Gitte Lund

AU - Bentzen, Bo Hjort

AU - Liang, Bo

AU - Aplin, Mark

AU - Grunnet, Morten

AU - Hansen, Jakob Lerche

AU - Jespersen, Thomas

PY - 2012/8

Y1 - 2012/8

N2 - Angiotensin II (AngII) is a key peptide in cardiovascular homeostasis and is a ligand for the Angiotensin II type 1 and 2 seven transmembrane receptors (AT 1 R and AT 2 R). The AT 1 receptor is a seven-transmembrane (7TM) G protein-coupled receptor (GPCR) mediating the majority of the physiological functions of AngII. The AT 1 R mediates its effects through both G protein-dependent and independent signaling, which can be separated by functionally selective agonists. In the present study we investigate the effect of AngII and the β-arrestin biased agonist [SII]AngII on ischemia-reperfusion injury in rat hearts. Isolated hearts mounted in a Langendorff perfused rat heart preparations showed that preconditioning with [SII]AngII reduced the infarct size induced by global ischemia from 46±8.4% to 22±3.4%. In contrast, neither preconditioning with AngII nor postconditioning with AngII or [SII]AngII had a protective effect. Together these results demonstrate a cardioprotective effect of simultaneous blockade of G protein signaling and activation of G protein independent signaling through AT 1 receptors.

AB - Angiotensin II (AngII) is a key peptide in cardiovascular homeostasis and is a ligand for the Angiotensin II type 1 and 2 seven transmembrane receptors (AT 1 R and AT 2 R). The AT 1 receptor is a seven-transmembrane (7TM) G protein-coupled receptor (GPCR) mediating the majority of the physiological functions of AngII. The AT 1 R mediates its effects through both G protein-dependent and independent signaling, which can be separated by functionally selective agonists. In the present study we investigate the effect of AngII and the β-arrestin biased agonist [SII]AngII on ischemia-reperfusion injury in rat hearts. Isolated hearts mounted in a Langendorff perfused rat heart preparations showed that preconditioning with [SII]AngII reduced the infarct size induced by global ischemia from 46±8.4% to 22±3.4%. In contrast, neither preconditioning with AngII nor postconditioning with AngII or [SII]AngII had a protective effect. Together these results demonstrate a cardioprotective effect of simultaneous blockade of G protein signaling and activation of G protein independent signaling through AT 1 receptors.

U2 - 10.1159/000341445

DO - 10.1159/000341445

M3 - Journal article

C2 - 22854413

SN - 1015-8987

VL - 30

SP - 642

EP - 652

JO - Cellular Physiology and Biochemistry

JF - Cellular Physiology and Biochemistry

IS - 3

ER -

Functionally Selective AT(1) Receptor Activation Reduces Ischemia Reperfusion Injury

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