Linked Life Data

19023131

Source:http://linkedlifedata.com/resource/pubmed/id/19023131

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2009-1-1
pubmed:abstractText
Previous studies demonstrated increased fatty acid uptake and metabolism in MHC-FATP transgenic mice that overexpress fatty acid transport protein (FATP)1 in the heart under the control of the alpha-myosin heavy chain (alpha-MHC) promoter. Doppler tissue imaging and hemodynamic measurements revealed diastolic dysfunction, in the absence of changes in systolic function. The experiments here directly test the hypothesis that the diastolic dysfunction in MHC-FATP mice reflects impaired ventricular myocyte contractile function. In vitro imaging of isolated adult MHC-FATP ventricular myocytes revealed that mean diastolic sarcomere length is significantly (P<0.01) shorter than in wild-type (WT) cells (1.79+/-0.01 versus 1.84+/-0.01 microm). In addition, the relaxation rate (dL/dt) is significantly (P<0.05) slower in MHC-FATP than WT myocytes (1.58+/-0.09 versus 1.92+/-0.13 microm/s), whereas both fractional shortening and contraction rates are not different. Application of 40 mmol/L 2,3-butadionemonoxime (a nonspecific ATPase inhibitor that relaxes actin-myosin interactions) increased diastolic sarcomere length in both WT and MHC-FATP myocytes to the same length, suggesting that MHC-FATP myocytes are partially activated at rest. Direct measurements of intracellular Ca(2+) revealed that diastolic [Ca(2+)](i) is unchanged in MHC-FATP myocytes and the rate of calcium removal is unexpectedly faster in MHC-FATP than WT myocytes. Moreover, diastolic sarcomere length in MHC-FATP and WT myocytes was unaffected by removal of extracellular Ca(2+) or by buffering of intracellular Ca(2+) with the Ca(2+) chelator BAPTA (100 micromol/L), indicating that elevated intracellular Ca(2+) does not underlie impaired diastolic function in MHC-FATP ventricular myocytes. Functional assessment of skinned myocytes, however, revealed that myofilament Ca(2+) sensitivity is markedly increased in MHC-FATP, compared with WT, ventricular cells. In addition, biochemical experiments demonstrated increased expression of the beta-MHC isoform in MHC-FATP, compared with WT ventricles, which likely contributes to the slower relaxation rate observed in MHC-FATP myocytes. Collectively, these data demonstrate that derangements in lipid metabolism in MHC-FATP ventricles, which are similar to those observed in the diabetic heart, result in impaired diastolic function that primarily reflects changes in myofilament function, rather than altered Ca(2+) cycling.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
1524-4571
pubmed:author
pubmed:issnType
Electronic
pubmed:day
2
pubmed:volume
104
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
95-103
pubmed:meshHeading
pubmed-meshheading:19023131-Animals, pubmed-meshheading:19023131-Calcium, pubmed-meshheading:19023131-Chelating Agents, pubmed-meshheading:19023131-Diabetes Complications, pubmed-meshheading:19023131-Diacetyl, pubmed-meshheading:19023131-Diastole, pubmed-meshheading:19023131-Disease Models, Animal, pubmed-meshheading:19023131-Egtazic Acid, pubmed-meshheading:19023131-Fatty Acid Transport Proteins, pubmed-meshheading:19023131-Fatty Acids, pubmed-meshheading:19023131-Heart Failure, Diastolic, pubmed-meshheading:19023131-Heart Ventricles, pubmed-meshheading:19023131-Isometric Contraction, pubmed-meshheading:19023131-Mice, pubmed-meshheading:19023131-Mice, Transgenic, pubmed-meshheading:19023131-Myocardial Contraction, pubmed-meshheading:19023131-Myocardium, pubmed-meshheading:19023131-Myocytes, Cardiac, pubmed-meshheading:19023131-Myosin Heavy Chains, pubmed-meshheading:19023131-Recombinant Fusion Proteins, pubmed-meshheading:19023131-Sarcomeres
pubmed:year
2009
pubmed:articleTitle
Ca2+-independent alterations in diastolic sarcomere length and relaxation kinetics in a mouse model of lipotoxic diabetic cardiomyopathy.
pubmed:affiliation
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO 63110, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't