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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
5
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pubmed:dateCreated |
2008-5-9
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pubmed:abstractText |
Restrictive cardiomyopathy (RCM) is a debilitating disease characterized by impaired ventricular filling, reduced ventricular volumes, and severe diastolic dysfunction. Hypertrophic cardiomyopathy (HCM) is characterized by ventricular hypertrophy and heightened risk of premature sudden cardiac death. These cardiomyopathies can result from mutations in the same gene that encodes for cardiac troponin I (cTnI). Acute genetic engineering of adult rat cardiac myocytes was used to ascertain whether primary physiologic outcomes could distinguish between RCM and HCM alleles at the cellular level. Co-transduction of cardiac myocytes with wild-type (WT) cTnI and RCM/HCM linked mutants in cTnI's inhibitory region (IR) demonstrated that WT cTnI preferentially incorporated into the sarcomere over IR mutants. The cTnI IR mutants exhibited minor effects in single myocyte Ca(2+)-activated tension assays yet prolonged relaxation and Ca(2+) decay. In comparison RCM cTnI mutants in the helix-4/C-terminal region demonstrated a) hyper-sensitivity to Ca(2+) under loaded conditions, b) slowed myocyte mechanical relaxation and Ca(2+) transient decay, c) frequency-dependent Ca(2+)-independent diastolic tone, d) heightened myofilament incorporation and e) irreversible cellular contractile defects with acute diltiazem administration. For species comparison, a subset of cTnI mutants were tested in isolated adult rabbit cardiac myocytes. Here, RCM and HCM mutant cTnIs exerted similar effects of slowed myocyte relaxation and Ca(2+) transient decay but did not show variable phenotypes by cTnI region. This study highlights cellular contractile defects by cardiomyopathy mutant cTnIs that are allele and species dependent. The species dependent results in particular raise important issues toward elucidating a unifying mechanistic pathway underlying the inherited cardiomyopathies.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/18423659-10385527,
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http://linkedlifedata.com/resource/pubmed/commentcorrection/18423659-9379958
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
1095-8584
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:volume |
44
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
891-904
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:18423659-Animals,
pubmed-meshheading:18423659-Calcium,
pubmed-meshheading:18423659-Rats,
pubmed-meshheading:18423659-Mutation,
pubmed-meshheading:18423659-Rabbits,
pubmed-meshheading:18423659-Female,
pubmed-meshheading:18423659-Male,
pubmed-meshheading:18423659-Permeability,
pubmed-meshheading:18423659-Species Specificity,
pubmed-meshheading:18423659-Myocardial Contraction,
pubmed-meshheading:18423659-Cardiomyopathy, Hypertrophic,
pubmed-meshheading:18423659-Rats, Sprague-Dawley,
pubmed-meshheading:18423659-Alleles,
pubmed-meshheading:18423659-Actin Cytoskeleton,
pubmed-meshheading:18423659-Sarcomeres,
pubmed-meshheading:18423659-Cardiac Pacing, Artificial,
pubmed-meshheading:18423659-Protein Transport,
pubmed-meshheading:18423659-Protein Structure, Tertiary,
pubmed-meshheading:18423659-Myocytes, Cardiac,
pubmed-meshheading:18423659-Calcium Signaling,
pubmed-meshheading:18423659-Troponin I,
pubmed-meshheading:18423659-Gene Targeting,
pubmed-meshheading:18423659-Mutant Proteins
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