Sepsis-induced myocardial depression is associated with transcriptional changes in energy metabolism and contractile related genes: a physiological and gene expression-based approach.
BACKGROUND
Increased nitric oxide production and altered mitochondrial function have been implicated in sepsis-induced cardiac dysfunction. The molecular mechanisms underlying myocardial depression in sepsis and the contribution of nitric oxide in this process however, are incompletely understood.


OBJECTIVE
To assess the transcriptional profile associated with sepsis-induced myocardial depression in a clinically relevant mouse model, and specifically test the hypothesis that critical transcriptional changes are inducible nitric oxide synthase-dependent.


METHODS
Laboratory investigation.


METHODS
University affiliated research laboratory.


METHODS
C57/BL6 wild type and congenic B6 129P2-Nos2tm1Lau/J (iNOS) mice.


METHODS
Assessment of myocardial function after 48 hrs of induction of polymicrobial sepsis by caecal ligation and perforation.


RESULTS
We compared the myocardial transcriptional profile in C57/BL6 wild type mice and congenic B6 129P2-Nos2tm1Lau/J litter mates after 48 hrs of polymicrobial sepsis induced by caecal ligation and perforation. Profiling of 22,690 expressed sequence tags by gene set enrichment analysis demonstrated that inducible nitric oxide synthase -/- failed to down regulate critical bioenergy and metabolism related genes including the gene for peroxisome proliferator-activated receptor gamma coactivator 1. Bioinformatics analysis identified a striking concordance in down regulation of transcriptional activity of proliferator-activated receptor gamma coactivator 1-related transcription factors resulting in sepsis associated myocardial remodeling as shown by isoform switching in the expression of contractile protein myosin heavy chain. In inducible nitric oxide synthase -/- deficient mice, contractile depression was minimal, and the transcriptional switch was absent.


CONCLUSIONS
Metabolic and myosin isoform gene expression switch in sepsis-induced myocardial depression is inducible nitric oxide synthase-dependent. Furthermore, we suggest that the molecular switch favoring the expression of fetal isoforms of contraction related proteins is associated with regulation of proliferator-activated receptor gamma coactivator 1 and related transcription factors in an inducible nitric oxide synthase-dependent manner.
dos Santos
Claudia C
CC
Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada.
Gattas
David J
DJ
Tsoporis
James N
JN
Smeding
Lonneke
L
Kabir
Golam
G
Masoom
Hussain
H
Akram
Ali
A
Plotz
Frans
F
Slutsky
Arthur S
AS
Husain
Mansoor
M
Sibbald
William J
WJ
Parker
Thomas G
TG
D000818:Animals; D024722:Cardiac Myosins / Q000235:genetics*; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000235:genetics* / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics* / Q000502:physiology; D006333:Heart Failure / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009200:Myocardial Contraction / Q000235:genetics* / Q000502:physiology; D018995:Myosin Heavy Chains / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D018805:Sepsis / Q000235:genetics* / Q000503:physiopathology; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics* / Q000502:physiology; D020257:Ventricular Remodeling / Q000235:genetics / Q000502:physiology
D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains