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Cardiac-directed parvalbumin transgene expression in mice shows marked heart rate dependence of delayed Ca2+ buffering action
- Source :
- Physiological genomics. 33(3)
- Publication Year :
- 2008
-
Abstract
- Relaxation abnormalities are prevalent in heart failure and contribute to clinical outcomes. Disruption of Ca2+homeostasis in heart failure delays relaxation by prolonging the intracellular Ca2+transient. We sought to speed cardiac relaxation in vivo by cardiac-directed transgene expression of parvalbumin (Parv), a cytosolic Ca2+buffer normally expressed in fast-twitch skeletal muscle. A key feature of Parv's function resides in its Ca2+/Mg2+binding affinities that account for delayed Ca2+buffering in response to the intracellular Ca2+transient. Cardiac Parv expression decreased sarcoplasmic reticulum Ca2+content without otherwise altering intracellular Ca2+homeostasis. At high physiological mouse heart rates in vivo, Parv modestly accelerated relaxation without affecting cardiac morphology or systolic function. Ex vivo pacing of the isolated heart revealed a marked heart rate dependence of Parv's delayed Ca2+buffering effects on myocardial performance. As the pacing frequency was lowered (7 to 2.5 Hz), the relaxation rates increased in Parv hearts. However, as pacing rates approached the dynamic range in humans, Parv hearts demonstrated decreased contractility, consistent with Parv buffering systolic Ca2+. Mathematical modeling and in vitro studies provide the underlying mechanism responsible for the frequency-dependent fractional Ca2+buffering action of Parv. Future studies directed toward refining the dose and frequency-response relationships of Parv in the heart or engineering novel Parv-based Ca2+buffers with modified Mg2+and Ca2+affinities to limit systolic Ca2+buffering may hold promise for the development of new therapies to remediate relaxation abnormalities in heart failure.
- Subjects :
- medicine.medical_specialty
Physiology
Diastole
Gene Expression
Mice, Transgenic
Buffers
Mice
Organ Culture Techniques
Heart Rate
Internal medicine
Heart rate
Genetics
medicine
Animals
Homeostasis
Humans
Myocytes, Cardiac
Calcium Signaling
Transgenes
biology
Myocardium
Cardiac Pacing, Artificial
Models, Cardiovascular
Skeletal muscle
medicine.disease
Myocardial Contraction
Rats
Mice, Inbred C57BL
Sarcoplasmic Reticulum
Endocrinology
medicine.anatomical_structure
Parvalbumins
Organ Specificity
Heart failure
biology.protein
Calcium
Parvalbumin
Intracellular
Ex vivo
Subjects
Details
- ISSN :
- 15312267
- Volume :
- 33
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Physiological genomics
- Accession number :
- edsair.doi.dedup.....baa5853ae488376115ed0823d6c7bb7f