Protein Overexpression at Heart of Heart Failure
Chronic heart failure resulting from dilated cardiomyopathy is rapidly emerging as a disease of epidemic proportions.1 Molecular mechanisms are being studied and advances have been made in a minority of cases, e.g.: the familial forms.
Intracellular [Ca2+]i homeostasis is essential for normal cardiac function and integrity, and dysregulation of [Ca2+]i is a hallmark of advanced heart failure.2 The primary trigger for cardiac [Ca2+]i transients is calcium entry through the pore subunit of the voltage-dependent L-type channels (L-VDCC), but their role in heart failure is still controversial. Electrophysiological studies on individual L-VDCCs from failing human heart have revealed an increased single-channel activity but the mechanism for this biophysical phenotype has remained unknown.3,4
In a paper in this week’s PLoS ONE, Roger Hullin of the Swiss Heart Center Bern, Jan Matthes of University of Cologne, Germany, and collaborators in both Germany and the USA demonstrate an up-regulation of expression of an accessory subunit of the L-VDCC complex (beta 2-subunit) that is responsible for the altered channel behavior in human heart failure. Similar changes of both beta 2-subunit expression and single-channel behavior were also observed in a mouse model of heart failure with cardiac overexpression of the human L-type Ca2+-channel pore. The causal role of the increased beta 2-subunit expression for the “heart failure type” of single L-VDCC characteristics was proven when the authors developed a novel, cardiac-specific, drug-inducible beta 2a subunit overexpression transgenic mouse which was crossbred with the channel pore overexpressing mouse when still nonfailing (“Adaptive phase”). In the nonfailing double transgenics, the induction of beta 2a protein expression increased the activity of single ventricular L-VDCC, rendering these channels phenotypically identical to human and mouse heart failure.
The authors conclude that electrical remodeling of the L-VDCC, based on gene expression changes, is an early step in a cascade ultimately induced in heart failure. This provides a rational framework for novel therapeutic intervention in heart failure.
1.Kannel WB (2000) Incidence and epidemiology of heart failure. Heart Fail Rev 5: 167-73.
2.Sjaastad I et al. (2003) Heart failure - a challenge to our current concepts of excitation-contraction coupling. J Physiol 546: 33-47.
3.Schroeder F et al. (1998) Increased availability and open probability of single L-type calcium channels from failing compared with nonfailing human ventricle. Circulation 98: 969-76.
4.Bodi I et al. (2005) The L-type calcium channel in the heart: the beat goes on. J Clin Invest 115: 3306-17.
Andrew Hyde | alfa
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