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Published on: May 27, 2010
Alterations of L-type calcium current and cardiac function in CaMKII{delta} knockout mice
Lin Xu1, Dongwu Lai, Jun Cheng
1Department of Pediatrics and Children's Healthcare of Atlanta, Emory University, GA, USA.
Rationale:
Recent studies have highlighted important roles of CaMKII in regulating Ca(2+) handling and excitation-contraction coupling. However, the cardiac effect of chronic CaMKII inhibition has not been well understood.
Objective:
We have tested the alterations of L-type calcium current (I(Ca)) and cardiac function in CaMKIIdelta knockout (KO) mouse left ventricle (LV).
Methods And Results:
We used the patch-clamp method to record I(Ca) in ventricular myocytes and found that in KO LV, basal I(Ca) was significantly increased without changing the transmural gradient of I(Ca) distribution. Substitution of Ba(2+) for Ca(2+) showed similar increase in I(Ba). There was no change in the voltage dependence of I(Ca) activation and inactivation. I(Ca) recovery from inactivation, however, was significantly slowed. In KO LV, the Ca(2+)-dependent I(Ca) facilitation (CDF) and I(Ca) response to isoproterenol (ISO) were significantly reduced. However, ISO response was reversed by beta2-adrenergic receptor (AR) inhibition. Western blots showed a decrease in beta1-AR and an increase in Ca(v)1.2, beta2-AR, and Galphai3 protein levels. Ca(2+) transient and sarcomere shortening in KO myocytes were unchanged at 1-Hz but reduced at 3-Hz stimulation. Echocardiography in conscious mice revealed an increased basal contractility in KO mice. However, cardiac reserve to work load and beta-adrenergic stimulation was reduced. Surprisingly, KO mice showed a reduced heart rate in response to work load or beta-adrenergic stimulation.
Conclusions:
Our results implicate physiological CaMKII activity in maintaining normal I(Ca), Ca(2+) handling, excitation-contraction coupling, and the in vivo heart function in response to cardiac stress.
Insights
Chronic inhibition of CaMKII in mice alters L-type calcium current and cardiac function. This study reveals CaMKII’s crucial role in maintaining normal heart function under stress.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Calcium Signaling
Background:
- Calcium/calmodulin-dependent protein kinase II (CaMKII) is vital for calcium handling and excitation-contraction coupling.
- The long-term effects of CaMKII inhibition on cardiac function remain incompletely understood.
Purpose of the Study:
- To investigate the impact of CaMKIIdelta knockout (KO) on L-type calcium current (I(Ca)) and cardiac function in mouse left ventricles (LV).
Main Methods:
- Patch-clamp electrophysiology to record I(Ca) in ventricular myocytes.
- Analysis of protein expression via Western blots.
- Echocardiography to assess cardiac function in vivo.
Main Results:
- KO LV exhibited increased basal I(Ca) with slowed recovery from inactivation.
- Ca(2+)-dependent I(Ca) facilitation and isoproterenol response were reduced in KO myocytes.
- KO mice showed increased basal contractility but impaired cardiac reserve and reduced heart rate response to stress.
Conclusions:
- Physiological CaMKII activity is essential for normal I(Ca) and cardiac function.
- CaMKII plays a critical role in excitation-contraction coupling and in vivo heart performance during stress.
