Day Sharlene M, Coutu Pierre, Wang Wang, Herron Todd, Turner Immanuel, Shillingford Michael, Lacross Nathan C, Converso Kimber L, Piao Lin, Li Jingdong, Lopatin Anatoli N, Metzger Joseph M
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0644, USA.
Physiol Genomics. 2008 May 13;33(3):312-22. doi: 10.1152/physiolgenomics.00302.2007. Epub 2008 Mar 11.
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.
舒张功能异常在心力衰竭中普遍存在，并影响临床预后。心力衰竭时钙离子稳态的破坏通过延长细胞内钙离子瞬变来延迟舒张。我们试图通过在心脏定向转基因表达小白蛋白（Parv）来加速体内心脏舒张，小白蛋白是一种通常在快肌骨骼肌中表达的胞质钙离子缓冲蛋白。Parv功能的一个关键特征在于其钙/镁结合亲和力，这导致了对细胞内钙离子瞬变的延迟钙缓冲。心脏Parv表达降低了肌浆网钙含量，但未改变细胞内钙离子稳态。在体内小鼠心脏的高生理心率下，Parv适度加速了舒张，而不影响心脏形态或收缩功能。离体心脏的体外起搏显示，Parv对心肌性能的延迟钙缓冲作用有明显的心率依赖性。随着起搏频率降低（7至2.5Hz），Parv心脏的舒张速率增加。然而，当起搏速率接近人类的动态范围时，Parv心脏表现出收缩力下降，这与Parv缓冲收缩期钙离子一致。数学建模和体外研究提供了Parv频率依赖性部分钙缓冲作用的潜在机制。未来的研究旨在优化Parv在心脏中的剂量和频率反应关系，或设计具有修饰镁和钙亲和力的新型基于Parv的钙缓冲剂以限制收缩期钙缓冲，这可能为开发治疗心力衰竭舒张功能异常的新疗法带来希望。
