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Original articles
Published online: 2017-08-21
Submitted: 2016-11-19
Accepted: 2017-07-25
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The endothelial nitric oxide synthase cofactor tetrahydrobiopterin shields the remote myocardium from apoptosis after experimental myocardial infarction in vivo

Felix M. Heidrich, Marcel C. Jercke, Anna Ritzkat, Annette Ebner, David M. Poitz, Christian Pfluecke, Silvio Quick, Uwe Speiser, Gregor Simonis, Nadine K. Wäßnig, Ruth H. Strasser, Stephan Wiedemann
DOI: 10.5603/KP.a2017.0164

open access

Ahead of print
Original articles
Published online: 2017-08-21
Submitted: 2016-11-19
Accepted: 2017-07-25

Abstract

Background: Following myocardial infarction (MI), apoptosis occurs early in the remote myocardium and contributes to the processes of myocardial remodeling. Increased nitrosative stress is a well-known and potent inductor of myocardial apoptosis. Excess activation of endothelial nitric oxide synthase (eNOS) increases its uncoupling potential and results in nitrosative stress via formation of peroxynitrite. However, the pathophysiologic role of eNOS signaling in the remote myocardium after MI is as yet undefined.

Aim: The impact of eNOS activation on pro- and anti-apoptotic signaling in the remote myocardium and the influence of pretreatment with the eNOS cofactor tetrahydrobiopterin (BH4) on eNOS activation, nitrosative stress level and apoptosis induction and execution were studied in a rat myocardial infarction model in vivo.

Results: 24 hours after anterior MI, eNOS activity in animals treated with left anterior descending coronary artery ligation (LIG) significantly increased in the posterior left ventricular myocardium as did protein nitrosylation when compared to sham treatment. This was paralleled by induction of apoptosis via both, the extrinsic and intrinsic pathways. Moreover, anti-apoptotic signaling via protein kinase B/Akt and glycogen synthase-kinase 3 beta was suppressed. Notably, pretreatment with the eNOS cofactor BH4 reduced eNOS activation, prevented excess protein nitrosylation, blunted apoptosis induction, facilitated anti-apoptotic signaling and eventually prevented apoptosis execution.

Conclusions: Here we showed that 24 hours after experimental MI in rats in vivo, apoptosis was induced in the posterior non-infarcted LV wall. Evidence is presented that pretreatment with the eNOS cofactor BH4 resulted in less nitrosative stress and weakened apoptotic processes, although stabilizers contained did participate in this phenomenon. Because apoptosis is a crucial component of myocardial remodeling, influencing eNOS signaling might be an interesting pharmacological target for the development of novel anti-remodeling therapies.

Abstract

Background: Following myocardial infarction (MI), apoptosis occurs early in the remote myocardium and contributes to the processes of myocardial remodeling. Increased nitrosative stress is a well-known and potent inductor of myocardial apoptosis. Excess activation of endothelial nitric oxide synthase (eNOS) increases its uncoupling potential and results in nitrosative stress via formation of peroxynitrite. However, the pathophysiologic role of eNOS signaling in the remote myocardium after MI is as yet undefined.

Aim: The impact of eNOS activation on pro- and anti-apoptotic signaling in the remote myocardium and the influence of pretreatment with the eNOS cofactor tetrahydrobiopterin (BH4) on eNOS activation, nitrosative stress level and apoptosis induction and execution were studied in a rat myocardial infarction model in vivo.

Results: 24 hours after anterior MI, eNOS activity in animals treated with left anterior descending coronary artery ligation (LIG) significantly increased in the posterior left ventricular myocardium as did protein nitrosylation when compared to sham treatment. This was paralleled by induction of apoptosis via both, the extrinsic and intrinsic pathways. Moreover, anti-apoptotic signaling via protein kinase B/Akt and glycogen synthase-kinase 3 beta was suppressed. Notably, pretreatment with the eNOS cofactor BH4 reduced eNOS activation, prevented excess protein nitrosylation, blunted apoptosis induction, facilitated anti-apoptotic signaling and eventually prevented apoptosis execution.

Conclusions: Here we showed that 24 hours after experimental MI in rats in vivo, apoptosis was induced in the posterior non-infarcted LV wall. Evidence is presented that pretreatment with the eNOS cofactor BH4 resulted in less nitrosative stress and weakened apoptotic processes, although stabilizers contained did participate in this phenomenon. Because apoptosis is a crucial component of myocardial remodeling, influencing eNOS signaling might be an interesting pharmacological target for the development of novel anti-remodeling therapies.

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Keywords

myocardial infarction; myocardial remodeling; apoptosis; endothelial nitric oxide synthase; nitric oxide; nitrosative stress

About this article
Title

The endothelial nitric oxide synthase cofactor tetrahydrobiopterin shields the remote myocardium from apoptosis after experimental myocardial infarction in vivo

Journal

Kardiologia Polska (Polish Heart Journal)

Issue

Ahead of print

Published online

2017-08-21

DOI

10.5603/KP.a2017.0164

Keywords

myocardial infarction
myocardial remodeling
apoptosis
endothelial nitric oxide synthase
nitric oxide
nitrosative stress

Authors

Felix M. Heidrich
Marcel C. Jercke
Anna Ritzkat
Annette Ebner
David M. Poitz
Christian Pfluecke
Silvio Quick
Uwe Speiser
Gregor Simonis
Nadine K. Wäßnig
Ruth H. Strasser
Stephan Wiedemann

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