Redox signaling and splicing dependent change in myosin phosphatase underlie early versus late changes in NO vasodilator reserve in a mouse LPS model of sepsis. Am J Physiol Heart Circ Physiol 2015 May 01;308(9):H1039-50
Date
03/01/2015Pubmed ID
25724497Pubmed Central ID
PMC4551119DOI
10.1152/ajpheart.00912.2014Scopus ID
2-s2.0-84929688878 (requires institutional sign-in at Scopus site) 19 CitationsAbstract
Microcirculatory dysfunction may cause tissue malperfusion and progression to organ failure in the later stages of sepsis, but the role of smooth muscle contractile dysfunction is uncertain. Mice were given intraperitoneal LPS, and mesenteric arteries were harvested at 6-h intervals for analyses of gene expression and contractile function by wire myography. Contractile (myosin and actin) and regulatory [myosin light chain kinase and phosphatase subunits (Mypt1, CPI-17)] mRNAs and proteins were decreased in mesenteric arteries at 24 h concordant with reduced force generation to depolarization, Ca(2+), and phenylephrine. Vasodilator sensitivity to DEA/nitric oxide (NO) and cGMP under Ca(2+) clamp were increased at 24 h after LPS concordant with a switch to Mypt1 exon 24- splice variant coding for a leucine zipper (LZ) motif required for PKG-1α activation of myosin phosphatase. This was reproduced by smooth muscle-specific deletion of Mypt1 exon 24, causing a shift to the Mypt1 LZ+ isoform. These mice had significantly lower resting blood pressure than control mice but similar hypotensive responses to LPS. The vasodilator sensitivity of wild-type mice to DEA/NO, but not cGMP, was increased at 6 h after LPS. This was abrogated in mice with a redox dead version of PKG-1α (Cys42Ser). Enhanced vasorelaxation in early endotoxemia is mediated by redox signaling through PKG-1α but in later endotoxemia by myosin phosphatase isoform shifts enhancing sensitivity to NO/cGMP as well as smooth muscle atrophy. Muscle atrophy and modulation may be a novel target to suppress microcirculatory dysfunction; however, inactivation of inducible NO synthase, treatment with the IL-1 antagonist IL-1ra, or early activation of α-adrenergic signaling did not suppressed this response.
Author List
Reho JJ, Zheng X, Asico LD, Fisher SAAuthor
John J. Reho Research Scientist II in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCyclic GMP
Cyclic GMP-Dependent Protein Kinase Type I
Disease Models, Animal
Dose-Response Relationship, Drug
Gene Expression Regulation
Genotype
Intracellular Signaling Peptides and Proteins
Isoenzymes
Lipopolysaccharides
Male
Mesenteric Arteries
Mice, Inbred C57BL
Mice, Knockout
Microcirculation
Muscle Proteins
Muscle, Smooth, Vascular
Muscular Atrophy
Myosin-Light-Chain Kinase
Myosin-Light-Chain Phosphatase
Nitric Oxide
Nitric Oxide Synthase Type II
Oxidation-Reduction
Phenotype
Phosphoproteins
RNA, Messenger
Sepsis
Signal Transduction
Time Factors
Vasoconstrictor Agents
Vasodilation
Vasodilator Agents