Augmented age-associated innate immune responses contribute to negative inotropic and lusitropic effects of lipopolysaccharide and interferon γ

Gisele O. Rosas, Susan J. Zieman, Maral Donabedian, Koenraad Vandegaer, Joshua Hare

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Innate immunity not only mediates early host defenses to infection, but also contributes to septic hemodynamic compromise through nitric oxide synthase (NOS2) induction and inhibition of cardiovascular adrenergic responses. Because of increased age-related susceptibility to sepsis, we hypothesized that hearts from old (28-29 months) adult rats would exhibit greater β-adrenergic hyporesponsiveness than young (6-8 months) following lipopolysaccharide (LPS, 6 mg/kg) with and without interferon γ (INF-γ, 5000 units). LPS/INF-γ depressed baseline +dP/dt and isoproterenol-stimulated inotropy in both old and young hearts. β-adrenergic inotropic (+dP/dt) and lusitropic responses were more depressed in old v young LPS/INF-γ hearts. Additionally isoproterenol-stimulated cAMP elaboration was less in old (1950 ± 160 fmol/min/g) v young (2440 ± 170 fmol/min/g, P=0.05) LPS/INF-γ hearts. LPS alone also depressed basal +dP/dt and prolonged myocardial relaxation in old and young hearts, but suppressed isoproterenol +dP/dt responses only in old hearts. Depressed β-adrenergic inotropic responses were augmented with the selective NOS2 inhibitor N-iminoethyl-L-lysine. To establish biochemical mechanisms for this, we tested whether induction of NOS2 and innate immune system receptors (CD14 and Toll-like receptor 4, TLR4) were enhanced in old v young hearts. Induction of myocardial NOS2 and CD14 (not present in control) by LPS/INF-γ was ∼2-3-fold greater in old compared to young animals. TLR4 was constitutively expressed in old and young hearts and was unaffected by LPS/INF-γ. These findings indicate that advanced age is associated with augmented cardiac β-adrenergic depression and enhanced CD14-NOS2 signaling in response to cytokines. Upregulation of cardiovascular innate immunity may have clinical implications for increased mortality in older individuals with systemic inflammatory response syndromes.

Original languageEnglish
Pages (from-to)1849-1859
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume33
Issue number10
DOIs
StatePublished - Oct 29 2001
Externally publishedYes

Fingerprint

Innate Immunity
Interferons
Lipopolysaccharides
Adrenergic Agents
Isoproterenol
Toll-Like Receptor 4
Systemic Inflammatory Response Syndrome
Nitric Oxide Synthase
Lysine
Immune System
Sepsis
Up-Regulation
Hemodynamics
Cytokines
Mortality
Infection

Keywords

  • Aging
  • Innate immune system
  • L-NIL
  • L-NMMA
  • Nitric oxide
  • Sepsis

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Augmented age-associated innate immune responses contribute to negative inotropic and lusitropic effects of lipopolysaccharide and interferon γ. / Rosas, Gisele O.; Zieman, Susan J.; Donabedian, Maral; Vandegaer, Koenraad; Hare, Joshua.

In: Journal of Molecular and Cellular Cardiology, Vol. 33, No. 10, 29.10.2001, p. 1849-1859.

Research output: Contribution to journalArticle

@article{260aae41066f4eb4a5d636ac2572c152,
title = "Augmented age-associated innate immune responses contribute to negative inotropic and lusitropic effects of lipopolysaccharide and interferon γ",
abstract = "Innate immunity not only mediates early host defenses to infection, but also contributes to septic hemodynamic compromise through nitric oxide synthase (NOS2) induction and inhibition of cardiovascular adrenergic responses. Because of increased age-related susceptibility to sepsis, we hypothesized that hearts from old (28-29 months) adult rats would exhibit greater β-adrenergic hyporesponsiveness than young (6-8 months) following lipopolysaccharide (LPS, 6 mg/kg) with and without interferon γ (INF-γ, 5000 units). LPS/INF-γ depressed baseline +dP/dt and isoproterenol-stimulated inotropy in both old and young hearts. β-adrenergic inotropic (+dP/dt) and lusitropic responses were more depressed in old v young LPS/INF-γ hearts. Additionally isoproterenol-stimulated cAMP elaboration was less in old (1950 ± 160 fmol/min/g) v young (2440 ± 170 fmol/min/g, P=0.05) LPS/INF-γ hearts. LPS alone also depressed basal +dP/dt and prolonged myocardial relaxation in old and young hearts, but suppressed isoproterenol +dP/dt responses only in old hearts. Depressed β-adrenergic inotropic responses were augmented with the selective NOS2 inhibitor N-iminoethyl-L-lysine. To establish biochemical mechanisms for this, we tested whether induction of NOS2 and innate immune system receptors (CD14 and Toll-like receptor 4, TLR4) were enhanced in old v young hearts. Induction of myocardial NOS2 and CD14 (not present in control) by LPS/INF-γ was ∼2-3-fold greater in old compared to young animals. TLR4 was constitutively expressed in old and young hearts and was unaffected by LPS/INF-γ. These findings indicate that advanced age is associated with augmented cardiac β-adrenergic depression and enhanced CD14-NOS2 signaling in response to cytokines. Upregulation of cardiovascular innate immunity may have clinical implications for increased mortality in older individuals with systemic inflammatory response syndromes.",
keywords = "Aging, Innate immune system, L-NIL, L-NMMA, Nitric oxide, Sepsis",
author = "Rosas, {Gisele O.} and Zieman, {Susan J.} and Maral Donabedian and Koenraad Vandegaer and Joshua Hare",
year = "2001",
month = "10",
day = "29",
doi = "10.1006/jmcc.2001.1448",
language = "English",
volume = "33",
pages = "1849--1859",
journal = "Journal of Molecular and Cellular Cardiology",
issn = "0022-2828",
publisher = "Academic Press Inc.",
number = "10",

}

TY - JOUR

T1 - Augmented age-associated innate immune responses contribute to negative inotropic and lusitropic effects of lipopolysaccharide and interferon γ

AU - Rosas, Gisele O.

AU - Zieman, Susan J.

AU - Donabedian, Maral

AU - Vandegaer, Koenraad

AU - Hare, Joshua

PY - 2001/10/29

Y1 - 2001/10/29

N2 - Innate immunity not only mediates early host defenses to infection, but also contributes to septic hemodynamic compromise through nitric oxide synthase (NOS2) induction and inhibition of cardiovascular adrenergic responses. Because of increased age-related susceptibility to sepsis, we hypothesized that hearts from old (28-29 months) adult rats would exhibit greater β-adrenergic hyporesponsiveness than young (6-8 months) following lipopolysaccharide (LPS, 6 mg/kg) with and without interferon γ (INF-γ, 5000 units). LPS/INF-γ depressed baseline +dP/dt and isoproterenol-stimulated inotropy in both old and young hearts. β-adrenergic inotropic (+dP/dt) and lusitropic responses were more depressed in old v young LPS/INF-γ hearts. Additionally isoproterenol-stimulated cAMP elaboration was less in old (1950 ± 160 fmol/min/g) v young (2440 ± 170 fmol/min/g, P=0.05) LPS/INF-γ hearts. LPS alone also depressed basal +dP/dt and prolonged myocardial relaxation in old and young hearts, but suppressed isoproterenol +dP/dt responses only in old hearts. Depressed β-adrenergic inotropic responses were augmented with the selective NOS2 inhibitor N-iminoethyl-L-lysine. To establish biochemical mechanisms for this, we tested whether induction of NOS2 and innate immune system receptors (CD14 and Toll-like receptor 4, TLR4) were enhanced in old v young hearts. Induction of myocardial NOS2 and CD14 (not present in control) by LPS/INF-γ was ∼2-3-fold greater in old compared to young animals. TLR4 was constitutively expressed in old and young hearts and was unaffected by LPS/INF-γ. These findings indicate that advanced age is associated with augmented cardiac β-adrenergic depression and enhanced CD14-NOS2 signaling in response to cytokines. Upregulation of cardiovascular innate immunity may have clinical implications for increased mortality in older individuals with systemic inflammatory response syndromes.

AB - Innate immunity not only mediates early host defenses to infection, but also contributes to septic hemodynamic compromise through nitric oxide synthase (NOS2) induction and inhibition of cardiovascular adrenergic responses. Because of increased age-related susceptibility to sepsis, we hypothesized that hearts from old (28-29 months) adult rats would exhibit greater β-adrenergic hyporesponsiveness than young (6-8 months) following lipopolysaccharide (LPS, 6 mg/kg) with and without interferon γ (INF-γ, 5000 units). LPS/INF-γ depressed baseline +dP/dt and isoproterenol-stimulated inotropy in both old and young hearts. β-adrenergic inotropic (+dP/dt) and lusitropic responses were more depressed in old v young LPS/INF-γ hearts. Additionally isoproterenol-stimulated cAMP elaboration was less in old (1950 ± 160 fmol/min/g) v young (2440 ± 170 fmol/min/g, P=0.05) LPS/INF-γ hearts. LPS alone also depressed basal +dP/dt and prolonged myocardial relaxation in old and young hearts, but suppressed isoproterenol +dP/dt responses only in old hearts. Depressed β-adrenergic inotropic responses were augmented with the selective NOS2 inhibitor N-iminoethyl-L-lysine. To establish biochemical mechanisms for this, we tested whether induction of NOS2 and innate immune system receptors (CD14 and Toll-like receptor 4, TLR4) were enhanced in old v young hearts. Induction of myocardial NOS2 and CD14 (not present in control) by LPS/INF-γ was ∼2-3-fold greater in old compared to young animals. TLR4 was constitutively expressed in old and young hearts and was unaffected by LPS/INF-γ. These findings indicate that advanced age is associated with augmented cardiac β-adrenergic depression and enhanced CD14-NOS2 signaling in response to cytokines. Upregulation of cardiovascular innate immunity may have clinical implications for increased mortality in older individuals with systemic inflammatory response syndromes.

KW - Aging

KW - Innate immune system

KW - L-NIL

KW - L-NMMA

KW - Nitric oxide

KW - Sepsis

UR - http://www.scopus.com/inward/record.url?scp=0034781712&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034781712&partnerID=8YFLogxK

U2 - 10.1006/jmcc.2001.1448

DO - 10.1006/jmcc.2001.1448

M3 - Article

C2 - 11603926

AN - SCOPUS:0034781712

VL - 33

SP - 1849

EP - 1859

JO - Journal of Molecular and Cellular Cardiology

JF - Journal of Molecular and Cellular Cardiology

SN - 0022-2828

IS - 10

ER -