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ABSTRACT: The processes of excitation-contraction (EC) coupling consume large amounts of energy that need to be replenished by oxidative phosphorylation in the mitochondria. Since Ca2+ activates key enzymes of the Krebs cycle in the mitochondrial matrix, it is important to understand the mechanisms and kinetics of mitochondrial Ca2+ uptake to delineate how in cardiac myocytes, energy supply is efficiently matched to demand. In recent years, the identification of various proteins involved in mitochondrial Ca2+ signalling and the tethering of mitochondria to the sarcoplasmic reticulum (SR) has considerably advanced the field and supported the concept of a mitochondrial Ca2+ microdomain, in which Ca2+ concentrations are high enough to overcome the low Ca2+ affinity of the principal mitochondrial Ca2+ uptake mechanism, the Ca2+ uniporter. Furthermore, defects in EC coupling that occur in heart failure disrupt SR-mitochondrial Ca2+ crosstalk and may cause energetic deficit and oxidative stress, both factors that are thought to be causally involved in the initiation and progression of the disease.
Cardiovascular research 03/2013; · 5.80 Impact Factor
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Stephan H Schirmer,
Achim Degen,
Magnus Baumhäkel,
Florian Custodis,
Lisa Schuh, Michael Kohlhaas,
Erik Friedrich,
Ferdinand Bahlmann,
Reinhard Kappl,
Christoph Maack,
Michael Böhm,
Ulrich Laufs
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ABSTRACT: Collateral arteries protect tissue from ischaemia. Heart rate correlates with vascular events in patients with arterial obstructive disease. Here, we tested the effect of heart-rate reduction (HRR) on collateral artery growth.
The I(f)-channel inhibitor ivabradine reduced heart rate by 11% in wild-type and 15% in apolipoprotein E (ApoE)(-/-) mice and restored endothelium-dependent relaxation in aortic rings of ApoE(-/-) mice. Microsphere perfusion and angiographies demonstrated that ivabradine did not change hindlimb perfusion in wild-type mice but improved perfusion in ApoE(-/-) mice from 40.5 ± 15.8-60.2 ± 18.5% ligated/unligated hindlimb. Heart rate reduction (13%) with metoprolol failed to improve endothelial function and perfusion. Protein expression of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS, and eNOS activity were increased in collateral tissue following ivabradine treatment of ApoE(-/-) mice. Co-treatment with nitric oxide-inhibitor N (G)-nitro-L-arginine methyl ester abolished the effects of ivabradine on arteriogenesis. Following ivabradine, classical inflammatory cytokine expression was lowered in ApoE(-/-) circulating mononuclear cells and in plasma, but unaltered in collateral-containing hindlimb tissue, where numbers of perivascular macrophages also remained unchanged. However, ivabradine reduced expression of anti-arteriogenic cytokines CXCL10and CXCL11 and of smooth muscle cell markers smoothelin and desmin in ApoE(-/-) hindlimb tissue. Endothelial nitric oxide synthase and inflammatory cytokine expression were unchanged in wild-type mice. Ivabradine did not affect cytokine production in HUVECs and THP1 mononuclear cells and had no effect on the membrane potential of HUVECs in patch-clamp experiments.
Ivabradine-induced HRR stimulates adaptive collateral artery growth. Important contributing mechanisms include improved endothelial function, eNOS activity, and modulation of inflammatory cytokine gene expression.
European Heart Journal 08/2011; 33(10):1223-31. · 10.48 Impact Factor
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ABSTRACT: In chronic heart failure, maladaptive remodeling of the left ventricle (LV) with systolic and diastolic dysfunction underlies the inability of the heart to pump sufficient blood to supply the body with blood and oxygen. Three integral aspects of this maladaptive LV remodeling are (1) defects in excitation-contraction (EC) coupling, particularly of cellular Ca(2+) and Na(+) homeostasis; (2) an energetic deficit; and (3) oxidative stress. Although these three aspects are often investigated separately from each other, their close and dynamic interplay are increasingly recognized. Central to this novel approach are mitochondria, which are the main source for cellular ATP, but also for reactive oxygen species, and their function is critically regulated by Ca(2+) and Na(+). Here, we review recent advances in our understanding of how maladaptive changes of EC coupling can contribute to the energetic deficit and oxidative stress, which may initiate a vicious cycle leading to progressive cardiac dysfunction.
Trends in cardiovascular medicine 04/2011; 21(3):69-73. · 4.37 Impact Factor
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ABSTRACT: BACKGROUND: In heart failure, the Na+-Ca²+ exchanger (NCX) is upregulated and mediates Ca²+ influx (instead of efflux) during the cardiac action potential. Although this partly compensates for impaired sarcoplasmic reticulum Ca²+ release and supports inotropy, the energetic consequences have never been considered. Because NCX-mediated Ca²+ influx is rather slow and mitochondrial Ca²+ uptake (which stimulates NADH production by the Krebs cycle) is thought to be facilitated by high Ca²+ gradients in a "mitochondrial Ca²+ microdomain," we speculated that NCX-mediated Ca²+ influx negatively affects the bioenergetic feedback response. Methods and Results- With the use of a patch-clamp-based approach in guinea-pig myocytes, cytosolic and mitochondrial Ca²+ ([Ca²+](c) and [Ca²+](m), respectively) was determined within the same cell after varying Ca²+ influx via L-type Ca²+ channels (I(Ca,L)) or the NCX. The efficiency of mitochondrial Ca²+ uptake, indexed by the slope of plotting [Ca²+](m) against [Ca²+](c) during each Ca²+ transient, was maximal during I(Ca,L)-triggered sarcoplasmic reticulum Ca²+ release. Depletion of sarcoplasmic reticulum Ca²+ load and increased contribution of the NCX to cytosolic Ca²+ influx independently reduced the efficiency of mitochondrial Ca²+ uptake. The upstroke velocity of cytosolic Ca²+ transients closely correlated with the efficiency of mitochondrial Ca²+ uptake. Despite comparable [Ca²+](c), sarcoplasmic reticulum Ca²+ release, but not NCX-mediated Ca²+ influx, led to stimulation of Ca²+-sensitive dehydrogenases of the Krebs cycle. Conclusions- Increased contribution of the NCX to cytosolic Ca²+ transients, which occurs in cardiac myocytes from failing hearts, impairs mitochondrial Ca²+ uptake and the bioenergetic feedback response. This mechanism could contribute to energy starvation of failing hearts.
Circulation 11/2010; 122(22):2273-80. · 14.74 Impact Factor
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ABSTRACT: Oxidative stress is causally linked to the progression of heart failure, and mitochondria are critical sources of reactive oxygen species in failing myocardium. We previously observed that in heart failure, elevated cytosolic Na(+) ([Na(+)](i)) reduces mitochondrial Ca(2+) ([Ca(2+)](m)) by accelerating Ca(2+) efflux via the mitochondrial Na(+)/Ca(2+) exchanger. Because the regeneration of antioxidative enzymes requires NADPH, which is indirectly regenerated by the Krebs cycle, and Krebs cycle dehydrogenases are activated by [Ca(2+)](m), we speculated that in failing myocytes, elevated [Na(+)](i) promotes oxidative stress.
We used a patch-clamp-based approach to simultaneously monitor cytosolic and mitochondrial Ca(2+) and, alternatively, mitochondrial H(2)O(2) together with NAD(P)H in guinea pig cardiac myocytes. Cells were depolarized in a voltage-clamp mode (3 Hz), and a transition of workload was induced by beta-adrenergic stimulation. During this transition, NAD(P)H initially oxidized but recovered when [Ca(2+)](m) increased. The transient oxidation of NAD(P)H was closely associated with an increase in mitochondrial H(2)O(2) formation. This reactive oxygen species formation was potentiated when mitochondrial Ca(2+) uptake was blocked (by Ru360) or Ca(2+) efflux was accelerated (by elevation of [Na(+)](i)). In failing myocytes, H(2)O(2) formation was increased, which was prevented by reducing mitochondrial Ca(2+) efflux via the mitochondrial Na(+)/Ca(2+) exchanger.
Besides matching energy supply and demand, mitochondrial Ca(2+) uptake critically regulates mitochondrial reactive oxygen species production. In heart failure, elevated [Na(+)](i) promotes reactive oxygen species formation by reducing mitochondrial Ca(2+) uptake. This novel mechanism, by which defects in ion homeostasis induce oxidative stress, represents a potential drug target to reduce reactive oxygen species production in the failing heart.
Circulation 03/2010; 121(14):1606-13. · 14.74 Impact Factor
