Cardiac-directed parvalbumin transgene expression in mice shows marked heart rate dependence of delayed Ca2+ buffering action.

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.

• Authors: Sharlene M Day, Pierre Coutu, Wang Wang, Todd Herron, Immanuel Turner, Michael Shillingford, Nathan C Lacross, Kimber L Converso, Lin Piao, Jingdong Li, Anatoli N Lopatin, Joseph M Metzger
• Journal: Physiological genomics (Physiol Genomics) Vol. 33 Issue 3 Pg. 312-22 (May 13 2008) ISSN: 1531-2267 [Electronic] United States
• PMID: 18334547 (Publication Type: Journal Article)

Chemical References

• Buffers
• Parvalbumins
• Calcium

Topics

• Animals
• Buffers
• Calcium (metabolism)
• Calcium Signaling (genetics, physiology)
• Cardiac Pacing, Artificial
• Gene Expression (genetics, physiology)
• Heart Rate (genetics, physiology)
• Homeostasis
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Models, Cardiovascular
• Myocardial Contraction (genetics, physiology)
• Myocardium (metabolism)
• Myocytes, Cardiac (metabolism)
• Organ Culture Techniques
• Organ Specificity (genetics)
• Parvalbumins (biosynthesis, genetics)
• Rats
• Sarcoplasmic Reticulum (metabolism)
• Transgenes