Nitrosative stress and pharmacological modulation of heart failure

doi:10.1016/j.tips.2005.04.003

Trends in Pharmacological Sciences

Volume 26, Issue 6, June 2005, Pages 302-310

https://doi.org/10.1016/j.tips.2005.04.003 Get rights and content

Dysregulation of nitric oxide (NO) and increased oxidative and nitrosative stress are implicated in the pathogenesis of heart failure. Peroxynitrite is a reactive oxidant that is produced from the reaction of nitric oxide with superoxide anion and impairs cardiovascular function through multiple mechanisms, including activation of matrix metalloproteinases (MMPs) and nuclear enzyme poly(ADP-ribose) polymerase (PARP). Recent studies suggest that the neutralization of peroxynitrite or pharmacological inhibition of MMPs and PARP are promising new approaches in the experimental therapy of various forms of myocardial injury. In this article, the role of nitrosative stress and downstream mechanisms, including activation of MMPs and PARP, in various forms of heart failure are discussed and novel emerging therapeutic strategies offered by neutralization of peroxynitrite and inhibition of MMPs and PARP in these pathophysiological conditions are reviewed.

Section snippets

Role of increased oxidative stress in heart failure

Acute heart failure and chronic heart failure (CHF) are major causes of hospitalization, morbidity and mortality worldwide. Several different mechanisms can lead to cardiac pump failure (Figure 1). These mechanisms result in a mismatch between the load applied to the heart and the energy needed for contraction, which leads to reduced contractile efficiency (Figure 1).

The pathomechanism of heart failure is complex and involves the activation of numerous secondary pathways (e.g. pathways

Role of increased nitrosative stress and dysregulation of nitric oxide synthase in heart failure

Cardiomyocytes, endocardial endothelium, coronary endothelium and cardiac nerves are all sources of nitric oxide (NO) produced by Ca²⁺-dependent NO synthase (NOS) enzymes. NO serves several important physiological roles in the regulation of cardiac function, including coronary vasodilatation, inhibition of platelet and neutrophil adhesion and activation, modulation of cardiac contractile function, and inhibition of cardiac oxygen consumption (reviewed in 4, 5, 6).

NO is necessary for normal

Mechanisms of peroxynitrite-induced cardiac and vascular dysfunction

There are multiple possible downstream targets of peroxynitrite (Table 1, Figure 2) (reviewed in 8, 9, 14). For example, peroxynitrite-induced tyrosine nitration can lead to dysfunctional nitrated proteins whereas peroxynitrite-induced oxidation of crucial sulfydryl groups can inhibit important enzymes in the mitochondrial respiratory chain. Indeed, peroxynitrite-mediated nitration of myofibrillar creatine kinase impairs myocardial contractility [10]. Furthermore, peroxynitrite-modified

Role of peroxynitrite-induced activation of matrix metalloproteinases

MMPs are a family of proteolytic enzymes that are best known for their ability to degrade and remodel the extracellular matrix. MMPs are now also recognized to have a variety of novel actions as proteases on substrates other than extracellular matrix proteins. They have important roles both under physiological (e.g. angiogenesis and remodeling of the endometrium) and pathophysiological (e.g. neutrophil infiltration, cancer cell invasion and connective tissue remodeling) conditions. In the

Role of poly(ADP-ribose) polymerase (PARP) activation

Poly(ADP-ribose) polymerase 1 (PARP-1) is the major isoform of a family of nuclear enzymes with multiple regulatory functions. PARP cleaves NAD⁺ to nicotinamide and ADP-ribose to form long branches of ADP-ribose polymers on nuclear target proteins. PARP activation exerts its pathophysiological effects via two principal mechanisms (reviewed in [35]). First, when PARP is activated by single-strand breaks in DNA, it catalyzes the cleavage of NAD⁺ into nicotinamide. As a result, in oxidatively or

Possibilities for future pharmacological interventions for the experimental therapy of heart failure

Although there is strong experimental evidence for the role of ROS and reactive nitrogen species in the development of the structural and functional changes of the failing myocardium, the results of clinical trials with antioxidants such as vitamin C, vitamin E and coenzyme Q10 are equivocal [1]. The reason for these findings might be related to the type of antioxidant used (relatively low reaction rate with the reactive species or non-catalytic antioxidant) and the dose of the antioxidant used

References (80)

C. Heymes
Increased myocardial NADPH oxidase activity in human heart failure
J. Am. Coll. Cardiol.
(2003)
H. Rubbo
Nitric oxide regulation of superoxide and peroxynitrite-dependent lipid peroxidation. Formation of novel nitrogen-containing oxidized lipid derivatives
J. Biol. Chem.
(1994)
C. Szabo
Multiple pathways of peroxynitrite cytotoxicity
Toxicol. Lett.
(2003)
T. Damy
Increased neuronal nitric oxide synthase-derived NO production in the failing human heart
Lancet
(2004)
M.J. Mihm et al.
Peroxynitrite-induced inhibition and nitration of cardiac myofibrillar creatine kinase
Biochimie
(2002)
M.J. Mihm
Effects of peroxynitrite on isolated cardiac trabeculae: selective impact on myofibrillar energetic controllers
Biochimie
(2003)
P. Pacher
Pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase may represent a novel therapeutic approach in chronic heart failure
J. Am. Coll. Cardiol.
(2002)
N. Keira
Lethal effect of cytokine-induced nitric oxide and peroxynitrite on cultured rat cardiac myocytes
J. Mol. Cell. Cardiol.
(2002)
Y. Hayashi
Leukocyte-depleted terminal blood cardioplegia provides superior myocardial protective effects in association with myocardium-derived nitric oxide and peroxynitrite production for patients undergoing prolonged aortic crossclamping for more than 120 minutes
J. Thorac. Cardiovasc. Surg.
(2003)
U. Mehlhorn
Nitrotyrosine and 8-isoprostane formation indicate free radical-mediated injury in hearts of patients subjected to cardioplegia
J. Thorac. Cardiovasc. Surg.
(2003)

T. Okamoto

Activation of matrix metalloproteinases by peroxynitrite-induced protein S-glutathiolation via disulfide S-oxide formation

J. Biol. Chem.

(2001)

P. Pacher

Role of poly(ADP-ribose) polymerase activation in endotoxin-induced cardiac collapse in rodents

Biochem. Pharmacol.

(2002)

S. Lancel

Peroxynitrite decomposition catalysts prevent myocardial dysfunction and inflammation in endotoxemic rats

J. Am. Coll. Cardiol.

(2004)

C. Di Filippo

M40403 prevents myocardial injury induced by acute hyperglycaemia in perfused rat heart

Eur. J. Pharmacol.

(2004)

G. Szabo

Poly-ADP-ribose polymerase inhibition protects against myocardial and endothelial reperfusion injury after hypothermic cardiac arrest

J. Thorac. Cardiovasc. Surg.

(2003)

C. Bianchi

A novel peroxynitrite decomposer catalyst (FP-15) reduces myocardial infarct size in an in vivo peroxynitrite decomposer and acute ischemia-reperfusion in pigs

Ann. Thorac. Surg.

(2002)

O. Szenczi

Poly(ADP-ribose) polymerase regulates myocardial calcium handling in doxorubicin-induced heart failure

Biochem. Pharmacol.

(2005)

T.M. Camp

Doxycycline ameliorates ischemic and border-zone remodeling and endothelial dysfunction after myocardial infarction in rats

J. Heart Lung Transplant.

(2004)

R. Ferrari

Oxidative stress during myocardial ischaemia and heart failure

Curr. Pharm. Des.

(2004)

C.E. Berry et al.

Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications

J. Physiol.

(2004)

J.M. Hare et al.

NO/redox disequilibrium in the failing heart and cardiovascular system

J. Clin. Invest.

(2005)

P.B. Massion

Nitric oxide and cardiac function: ten years after, and continuing

Circ. Res.

(2003)

W.J. Paulus et al.

Nitric oxide's role in the heart: control of beating or breathing?

Am. J. Physiol. Heart Circ. Physiol.

(2004)

I.V. Turko et al.

Protein nitration in cardiovascular diseases

Pharmacol. Rev.

(2002)

M.J. Mihm

Peroxynitrite induced nitration and inactivation of myofibrillar creatine kinase in experimental heart failure

Cardiovasc. Res.

(2001)

I.N. Mungrue

Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation, heart block, and sudden death

J. Clin. Invest.

(2002)

O. Gealekman

Role of myocardial inducible nitric oxide synthase in contractile dysfunction and beta-adrenergic hyporesponsiveness in rats with experimental volume-overload heart failure

Circulation

(2002)

P. Ferdinandy et al.

Nitric oxide, superoxide, and peroxynitrite in myocardial ischaemia-reperfusion injury and preconditioning

Br. J. Pharmacol.

(2003)

P. Pacher

Potent metalloporphyrin peroxynitrite decomposition catalyst protects against the development of doxorubicin-induced cardiac dysfunction

Circulation

(2003)

P. Bai

Matrix metalloproteinase activation is an early event in doxorubicin-induced cardiotoxicity

Oncol. Rep.

(2004)

A.A. Chaves

Cardiomyopathy in a murine model of AIDS: evidence of reactive nitrogen species and corroboration in human HIV/AIDS cardiac tissues

Cardiovasc. Res.

(2003)

A. Ceriello

Acute hyperglycemia induces nitrotyrosine formation and apoptosis in perfused heart from rat

Diabetes

(2002)

W.H. Lee

Influence of peroxynitrite on energy metabolism and cardiac function in a rat ischemia-reperfusion model

Am. J. Physiol. Heart Circ. Physiol.

(2003)

F.H. Khadour

Enhanced NO and superoxide generation in dysfunctional hearts from endotoxemic rats

Am. J. Physiol. Heart Circ. Physiol.

(2002)

M. Iqbal

Time course of nitric oxide, peroxynitrite and antioxidants in the endotoxemic heart

Crit. Care Med.

(2002)

C.Q. Gao

Matrix metalloproteinase-2 mediates cytokine-induced myocardial contractile dysfunction

Cardiovasc. Res.

(2003)

C.S.R. Baker

Repetitive myocardial stunning in pigs is associated with an increased formation of reactive nitrogen species

Heart

(2002)

C.S. Baker

Immunocytochemical evidence for inducible nitric oxide synthase and cyclooxygenase-2 expression with nitrotyrosine formation in human hibernating myocardium

Basic Res. Cardiol.

(2002)

A.A. Miller

Inducible nitric oxide synthase-derived superoxide contributes to hypereactivity in small mesenteric arteries from a rat model of chronic heart failure

Br. J. Pharmacol.

(2000)

P.C. Colombo

Endothelial cell activation in patients with decompensated heart failure

Circulation

(2005)

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Published by Elsevier Ltd.

Trends in Pharmacological Sciences

Nitrosative stress and pharmacological modulation of heart failure

Section snippets

Role of increased oxidative stress in heart failure

Role of increased nitrosative stress and dysregulation of nitric oxide synthase in heart failure

Mechanisms of peroxynitrite-induced cardiac and vascular dysfunction

Role of peroxynitrite-induced activation of matrix metalloproteinases

Role of poly(ADP-ribose) polymerase (PARP) activation

Possibilities for future pharmacological interventions for the experimental therapy of heart failure

J. Am. Coll. Cardiol.

J. Biol. Chem.

Toxicol. Lett.

Lancet

Biochimie

Biochimie

J. Am. Coll. Cardiol.

J. Mol. Cell. Cardiol.

J. Thorac. Cardiovasc. Surg.

J. Thorac. Cardiovasc. Surg.

J. Biol. Chem.

Biochem. Pharmacol.

J. Am. Coll. Cardiol.

Eur. J. Pharmacol.

J. Thorac. Cardiovasc. Surg.

Ann. Thorac. Surg.

Biochem. Pharmacol.

J. Heart Lung Transplant.

Oxidative stress during myocardial ischaemia and heart failure

Curr. Pharm. Des.

Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications

J. Physiol.

NO/redox disequilibrium in the failing heart and cardiovascular system

J. Clin. Invest.

Nitric oxide and cardiac function: ten years after, and continuing

Circ. Res.

Nitric oxide's role in the heart: control of beating or breathing?

Am. J. Physiol. Heart Circ. Physiol.

Protein nitration in cardiovascular diseases

Pharmacol. Rev.

Peroxynitrite induced nitration and inactivation of myofibrillar creatine kinase in experimental heart failure

Cardiovasc. Res.

Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation, heart block, and sudden death

J. Clin. Invest.

Role of myocardial inducible nitric oxide synthase in contractile dysfunction and beta-adrenergic hyporesponsiveness in rats with experimental volume-overload heart failure

Circulation

Nitric oxide, superoxide, and peroxynitrite in myocardial ischaemia-reperfusion injury and preconditioning

Br. J. Pharmacol.

Potent metalloporphyrin peroxynitrite decomposition catalyst protects against the development of doxorubicin-induced cardiac dysfunction

Circulation

Matrix metalloproteinase activation is an early event in doxorubicin-induced cardiotoxicity

Oncol. Rep.

Cardiomyopathy in a murine model of AIDS: evidence of reactive nitrogen species and corroboration in human HIV/AIDS cardiac tissues

Cardiovasc. Res.

Acute hyperglycemia induces nitrotyrosine formation and apoptosis in perfused heart from rat

Diabetes

Influence of peroxynitrite on energy metabolism and cardiac function in a rat ischemia-reperfusion model

Am. J. Physiol. Heart Circ. Physiol.

Enhanced NO and superoxide generation in dysfunctional hearts from endotoxemic rats

Am. J. Physiol. Heart Circ. Physiol.

Time course of nitric oxide, peroxynitrite and antioxidants in the endotoxemic heart

Crit. Care Med.

Matrix metalloproteinase-2 mediates cytokine-induced myocardial contractile dysfunction

Cardiovasc. Res.

Repetitive myocardial stunning in pigs is associated with an increased formation of reactive nitrogen species

Heart

Immunocytochemical evidence for inducible nitric oxide synthase and cyclooxygenase-2 expression with nitrotyrosine formation in human hibernating myocardium

Basic Res. Cardiol.

Inducible nitric oxide synthase-derived superoxide contributes to hypereactivity in small mesenteric arteries from a rat model of chronic heart failure

Br. J. Pharmacol.

Endothelial cell activation in patients with decompensated heart failure

Circulation