Journal article
Calmodulin kinase II inhibition protects against structural heart disease
Nature medicine, Vol.11(4), pp.409-417
04/2005
DOI: 10.1038/nm1215
PMID: 15793582
Abstract
Beta-adrenergic receptor (betaAR) stimulation increases cytosolic Ca(2+) to physiologically augment cardiac contraction, whereas excessive betaAR activation causes adverse cardiac remodeling, including myocardial hypertrophy, dilation and dysfunction, in individuals with myocardial infarction. The Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) is a recently identified downstream element of the betaAR-initiated signaling cascade that is linked to pathological myocardial remodeling and to regulation of key proteins involved in cardiac excitation-contraction coupling. We developed a genetic mouse model of cardiac CaMKII inhibition to test the role of CaMKII in betaAR signaling in vivo. Here we show CaMKII inhibition substantially prevented maladaptive remodeling from excessive betaAR stimulation and myocardial infarction, and induced balanced changes in excitation-contraction coupling that preserved baseline and betaAR-stimulated physiological increases in cardiac function. These findings mark CaMKII as a determinant of clinically important heart disease phenotypes, and suggest CaMKII inhibition can be a highly selective approach for targeting adverse myocardial remodeling linked to betaAR signaling.
Details
- Title: Subtitle
- Calmodulin kinase II inhibition protects against structural heart disease
- Creators
- Rong Zhang - Department of Medicine, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, Tennessee 37232-6300, USAMichelle S C KhooYuejin WuYingbo YangChad E GrueterGemin NiWilliam ThielSilvia GuatimosimEdward E Price JrLong-Sheng SongErnest C MaduAnisha N ShahTatiana A VishnivetskayaJames B AtkinsonVsevolod V GurevichGuy SalamaW J LedererRoger J ColbranMark E Anderson
- Resource Type
- Journal article
- Publication Details
- Nature medicine, Vol.11(4), pp.409-417
- DOI
- 10.1038/nm1215
- PMID
- 15793582
- NLM abbreviation
- Nat Med
- ISSN
- 1078-8956
- eISSN
- 1546-170X
- Grant note
- HL070250 / NHLBI NIH HHS GM63097 / NIGMS NIH HHS HL25675 / NHLBI NIH HHS HL36974 / NHLBI NIH HHS EY11500 / NEI NIH HHS HL67849 / NHLBI NIH HHS HL046681 / NHLBI NIH HHS MH63232 / NIMH NIH HHS HL70511 / NHLBI NIH HHS HL70709 / NHLBI NIH HHS
- Language
- English
- Date published
- 04/2005
- Academic Unit
- Cardiovascular Medicine; Craniofacial Anomalies Research Center; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984094555002771
Metrics
26 Record Views