Circulation Research
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The Rac and Rho Hall of Fame Over the last decade, the Rho family GTPases have gained considerable recognition as powerful regulators of actin cytoskeletal organization. As with many high profile signal transducers, these molecules soon attracted the attention of the cardiovascular research community. Shortly thereafter, two prominent members known as RhoA and Rac1 were linked to agonist-induced gene expression and myofilament organization using the isolated cardiomyocyte cell model. Subsequent creation of transgenic mouse lines provided evidence for more complex roles of RhoA and Rac1 signaling. Clues from in vitro and in vivo studies suggest the involvement of numerous downstream targets of RhoA and Rac1 signaling including serum response factor, NF-κB, and other transcription factors, myofilament proteins, ion channels, and reactive oxygen species generation. Which of these contribute to the observed phenotypic effects of enhanced RhoA and Rac activation in vivo remain to be determined. Current research efforts with a more translational focus have used statins or Rho kinase blockers to assess RhoA and Rac1 as targets for interventional approaches to blunt hypertrophy or heart failure. Generally, salutary effects on remodeling and ischemic damage are observed, but the broad specificity and multiple cellular targets for these drugs within the myocardium demands caution in interpretation. In this review, we assess the evolution of knowledge related to Rac1 and RhoA in the context of hypertrophy and heart failure and highlight the direction that future exploration will lead.
Circulation Research - Tập 98 Số 6 - Trang 730-742 - 2006
ATP-regulated K+ channels protect the myocardium against ischemia/reperfusion damage. The role of ATP-regulated K+ channels in protecting the myocardium against ischemia/reperfusion damage was explored using glibenclamide and pinacidil to block and activate the channels, respectively. Electrical and mechanical activity of arterially perfused guinea pig right ventricular walls was recorded simultaneously via an intracellular microelectrode and a force transducer. The preparations were subjected to either 1) 20 minutes of no-flow ischemia with or without glibenclamide (1 and 10 microM) followed by reperfusion, or 2) 30 minutes of no-flow ischemia with or without pinacidil (1 and 10 microM) followed by reperfusion. No-flow ischemia for 20 minutes produced changes in electrical and mechanical activity that were completely reversed on reperfusion; resting membrane potential declined by 13 +/- 1.2 mV, action potential duration at 90% repolarization (APD90) decreased by 62%, and developed tension fell by greater than 95%, but resting tension did not change significantly. Glibenclamide (10 microM) had no effect on activity during normal perfusion, but during ischemia, resting membrane potential fell slightly further (17 +/- 1.8 mV) and APD90 declined by only 24%. Developed tension declined more slowly and to a lesser extent, but resting tension rose significantly between 10 and 20 minutes of ischemia. Reperfusion of glibenclamide-treated tissues elicited arrhythmias (extrasystoles and tachycardia), and the preparations failed to recover mechanical function. Glibenclamide at 1 microM produced qualitatively similar effects, albeit less severe. After 30 minutes of no-flow ischemia in untreated tissues, resting tension increased by approximately 130% during the no-flow period. Reperfusion caused arrhythmias (extrasystoles, tachyarrhythmias, and fibrillation) and failed to restore resting or developed tension to preischemic levels. Pinacidil at 1 microM did not affect electrical or contractile function, but at 10 microM it had a negative inotropic effect, decreasing APD90 and developed tension by 5% and 18%, respectively. Both concentrations of the drug caused a faster and greater decline in APD90 during the no-flow period. Resting tension did not change during 30 minutes of no-flow ischemia in the presence of pinacidil, and reperfusion led to 85% and complete recovery of electrical and mechanical activity at 1 and 10 microM, respectively. The data indicate that glibenclamide enhances whereas pinacidil reduces myocardial damage caused by ischemia/reperfusion. The results are consistent with the hypothesis that activation of ATP-regulated K+ channels during ischemia is an important adaptive mechanism for protecting the myocardium when blood flow to the tissue is compromised.
Circulation Research - Tập 69 Số 3 - Trang 571-581 - 1991
Intra- and extracellular K+ and Na+ activities and resting membrane potential in sheep cardiac purkinje strands. K+- and Na+-selective liquid ion-exchanger microelectrodes were used to measure intracellular K+ activity (aK i) and intracellular Na+ activity (aNa i) of sheep cardiac Purkinje strands in different solutions. In Tyrode's solution with an extracellular K+ concentration ([K+]o) of 5.4 mM, aK i was between 80 and 140 mM and averaged 109.6 +/- 4.0 mM (mean +/- SE, 20 strands). The measured aK i was closely correlated with the resting membrane potential, so that the K+ equilibrium potential was always about 10 mV more negative. When [K+]o was lower than 5.4 mM, aK i fell, and when [K+]o was higher than 5.4 mM it increased, aNa i was between 4 and 12 mM, and averaged 6.6 +/- 0.6 mM (14 strands). Its variation was also correlated with resting potential. Over a wide range of [K+]o and extracellular Na+ concentrations ([Na+]o), the aiNa changes were such that Na+ equilibrium potential remained between +70 and +80 mV. The quiescent membrane behaved as a K+-electrode when [K+]o was higher than 5.4 mM. When [K+]o was low and [Na+]o was zero, then Ca2+ and perhaps Cl- contributed to the resting potential.
Circulation Research - Tập 47 Số 5 - Trang 692-700 - 1980
Potentiation of Ca <sup>2+</sup> Release by cADP-Ribose in the Heart Is Mediated by Enhanced SR Ca <sup>2+</sup> Uptake Into the Sarcoplasmic Reticulum
Abstract—
cADP-Ribose (cADPR) is a novel endogenous messenger that is believed to mobilize Ca
2+
from ryanodine-sensitive Ca
2+
stores. Despite intense research, the precise mechanism of action of cADPR remains uncertain, and experimental findings are contradictory. To elucidate the mechanism of cADPR action, we performed confocal Ca
2+
imaging in saponin-permeabilized rat ventricular myocytes. Exposure of the cells to cADPR resulted in a slow (>2 minutes) and steady increase in the frequency of Ca
2+
sparks. These effects on local release events were accompanied by a significant increase in sarcoplasmic reticulum (SR) Ca
2+
content. In comparison, sensitization of ryanodine receptors (RyRs) by caffeine, a true RyR agonist, caused a rapid (<1 second) and transient potentiation of Ca
2+
sparks followed by a decrease in SR Ca
2+
content. When the increase in the SR load was prevented by partial inhibition of the SR Ca
2+
with thapsigargin, cADPR failed to produce any increase in sparking activity. cADPR had no significant impact on activity of single cardiac RyRs incorporated into lipid bilayers. However, it caused a significant increase in the rate of Ca
2+
uptake by cardiac SR microsomes. Our results suggest that the primary target of cADPR is the SR Ca
2+
uptake mechanism. Potentiation of Ca
2+
release by cADPR is mediated by increased accumulation of Ca
2+
in the SR and subsequent luminal Ca
2+
-dependent activation of RyRs.
Circulation Research - Tập 89 Số 7 - Trang 614-622 - 2001
Inhibition and Rapid Recovery of Ca <sup>2+</sup> Current During Ca <sup>2+</sup> Release From Sarcoplasmic Reticulum in Guinea Pig Ventricular Myocytes
Abstract
We have investigated the modulation of the L-type Ca
2+
channel by Ca
2+
released from the sarcoplasmic reticulum (SR) in single guinea pig ventricular myocytes under whole-cell voltage clamp. [Ca
2+
]
i
was monitored by fura 2. By use of impermeant monovalent cations in intracellular and extracellular solutions, the current through Na
+
channels, K
+
channels, nonspecific cation channels, and the Na
+
-Ca
2+
exchanger was effectively blocked. By altering the amount of Ca
2+
loading of the SR, the time course of the Ca
2+
current (I
Ca
) could be studied during various amplitudes of Ca
2+
release. In the presence of a large Ca
2+
release, fast inhibition of I
Ca
occurred, whereas on relaxation of [Ca
2+
]
i
, fast recovery was observed. The time course of this transient inhibition of I
Ca
reflected the time course of [Ca
2+
]
i
. However, the inhibition seen in the first 50 ms, ie, the time of net Ca
2+
release from the SR, exceeded the inhibition observed later during the pulse, suggesting the existence of a higher [Ca
2+
] near the channel during this time. Transient inhibition of I
Ca
during Ca
2+
release was observed to a similar degree at all potentials. It could still be observed in the presence of intracellular ATP-γ-S and of cAMP. Therefore, we conclude that the modulation of I
Ca
by Ca
2+
release from the SR is not related to dephosphorylation. It could be related to a reduction in the driving force and to a direct inhibition of the channel by [Ca
2+
]
i
. The observation that the degree of inhibition does not depend on membrane potential suggests that the Ca
2+
binding site for this modulation is located outside the pore. The transient nature of the modulation of I
Ca
by Ca
2+
release will contribute to the recovery of I
Ca
during prolonged action potentials.
Circulation Research - Tập 76 Số 1 - Trang 102-109 - 1995
Luminal Ca <sup>2+</sup> Controls Termination and Refractory Behavior of Ca <sup>2+</sup> -Induced Ca <sup>2+</sup> Release in Cardiac Myocytes
Despite extensive research, the mechanisms responsible for the graded nature and early termination of Ca
2+
-induced Ca
2+
release (CICR) from the sarcoplasmic reticulum (SR) in cardiac muscle remain poorly understood. Suggested mechanisms include cytosolic Ca
2+
-dependent inactivation/adaptation and luminal Ca
2+
-dependent deactivtion of the SR Ca
2+
release channels/ryanodine receptors (RyRs). To explore the importance of cytosolic versus luminal Ca
2+
regulatory mechanisms in controlling CICR, we assessed the impact of intra-SR Ca
2+
buffering on global and local Ca
2+
release properties of patch-clamped or permeabilized rat ventricular myocytes. Exogenous, low-affinity Ca
2+
buffers (5 to 20 mmol/L ADA, citrate or maleate) were introduced into the SR by exposing the cells to “internal” solutions containing the buffers. Enhanced Ca
2+
buffering in the SR was confirmed by an increase in the total SR Ca
2+
content, as revealed by application of caffeine. At the whole-cell level, intra-SR [Ca
2+
] buffering dramatically increased the magnitude of Ca
2+
transients induced by
I
Ca
and deranged the smoothly graded
I
Ca
-SR Ca
2+
release relationship. The amplitude and time-to-peak of local Ca
2+
release events, Ca
2+
sparks, as well as the duration of local Ca
2+
release fluxes underlying sparks were increased up to 2- to 3-fold. The exogenous Ca
2+
buffers in the SR also reduced the frequency of repetitive activity observed at individual release sites in the presence of the RyR activator Imperatoxin A. We conclude that regulation of RyR openings by local intra-SR [Ca
2+
] is responsible for termination of CICR and for the subsequent restitution behavior of Ca
2+
release sites in cardiac muscle.
Circulation Research - Tập 91 Số 5 - Trang 414-420 - 2002
Sarcoplasmic Reticulum Ca <sup>2+</sup> Refilling Controls Recovery From Ca <sup>2+</sup> -Induced Ca <sup>2+</sup> Release Refractoriness in Heart Muscle
In cardiac muscle Ca
2+
-induced Ca
2+
release (CICR) from the sarcoplasmic reticulum (SR) is initiated by Ca
2+
influx via L-type Ca
2+
channels. At present, the mechanisms underlying termination of SR Ca
2+
release, which are required to ensure stable excitation-contraction coupling cycles, are not precisely known. However, the same mechanism leading to refractoriness of SR Ca
2+
release could also be responsible for the termination of CICR. To examine the refractoriness of SR Ca
2+
release, we analyzed Na
+
-Ca
2+
exchange currents reflecting cytosolic Ca
2+
signals induced by UV-laser flash-photolysis of caged Ca
2+
. Pairs of UV flashes were applied at various intervals to examine the time course of recovery from CICR refractoriness. In cardiomyocytes isolated from guinea-pigs and mice, β-adrenergic stimulation with isoproterenol-accelerated recovery from refractoriness by ≈2-fold. Application of cyclopiazonic acid at moderate concentrations (<10 μmol/L) slowed down recovery from refractoriness in a dose-dependent manner. Compared with cells from wild-type littermates, those from phospholamban knockout (PLB-KO) mice exhibited almost 5-fold accelerated recovery from refractoriness. Our results suggest that SR Ca
2+
refilling mediated by the SR Ca
2+
-pump corresponds to the rate-limiting step for recovery from CICR refractoriness. Thus, the Ca
2+
sensitivity of CICR appears to be regulated by SR Ca
2+
content, possibly resulting from a change in the steady-state Ca
2+
sensitivity and in the gating kinetics of the SR Ca
2+
release channels (ryanodine receptors). During Ca
2+
release, the concomitant reduction in Ca
2+
sensitivity of the ryanodine receptors might also underlie Ca
2+
spark termination by deactivation.
Circulation Research - Tập 95 Số 8 - Trang 807-813 - 2004
Asynchronous Ca <sup>2+</sup> Waves in Intact Venous Smooth Muscle
Abstract
—The rabbit inferior vena cava (IVC) is a large-capacitance vessel that displays typical contractile dose-response curves for caffeine and phenylephrine (PE). Using confocal microscopy on the endothelium-denuded IVC, we undertook experiments to correlate these whole-tissue contractile dose-response curves with changes in subcellular [Ca
2+
]
i
signals in the in situ vascular smooth muscle cells (VSMCs). We observed that both caffeine and PE initially elicited Ca
2+
waves in individual VSMCs. The [Ca
2+
]
i
in cells challenged with caffeine subsequently returned to baseline whereas the [Ca
2+
]
i
in cells challenged with PE exhibited repetitive asynchronous Ca
2+
waves. These [Ca
2+
]
i
oscillations were related to Ca
2+
release from the sarcoplasmic reticulum as they were inhibited by ryanodine and caffeine. The lack of synchronicity of the [Ca
2+
]
i
oscillations between VSMCs can explain the observed tonic contraction at the whole-tissue level. The nature of these Ca
2+
waves was further characterized. For caffeine, the amplitude was all-or-none in nature, with individual cells differing in sensitivity, leading to their recruitment at different concentrations of the agonist. This concentration dependency of recruitment appears to form the basis for the concentration dependency of caffeine-induced contraction. Furthermore, the speed of the Ca
2+
waves correlated positively with the concentration of caffeine. In the case of PE, we observed the same characteristics with respect to wave speed, amplitude, and recruitment. Increasing concentrations of PE also enhance the frequency of the [Ca
2+
]
i
oscillations. We therefore conclude that PE stimulates whole-tissue contractility through differential recruitment of VSMCs and enhancement of the frequency of asynchronous [Ca
2+
]
i
oscillations once the cells are recruited. The full text of this article is available at http://www.circresaha.org.
Circulation Research - Tập 86 Số 4 - 2000
Cyclic ADP-Ribose Is the Primary Trigger for Hypoxic Pulmonary Vasoconstriction in the Rat Lung In Situ
Abstract
—Hypoxic pulmonary vasoconstriction (HPV) is unique to pulmonary arteries, and it aids ventilation/perfusion matching. However, in diseases such as emphysema, HPV can promote hypoxic pulmonary hypertension. We recently showed that hypoxia constricts pulmonary arteries in part by increasing cyclic ADP-ribose (cADPR) accumulation in the smooth muscle and, thereby, Ca
2+
release by ryanodine receptors. We now report on the role of cADPR in HPV in isolated rat pulmonary arteries and in the rat lung in situ. In isolated pulmonary arteries, the membrane-permeant cADPR antagonist, 8-bromo-cADPR, blocked sustained HPV by blocking Ca
2+
release from smooth muscle ryanodine-sensitive stores in the sarcoplasmic reticulum. Most importantly, we showed that 8-bromo-cADPR blocks HPV induced by alveolar hypoxia in the ventilated rat lung in situ. Inhibition of HPV was achieved without affecting (1) constriction by membrane depolarization and voltage-gated Ca
2+
influx, (2) the release (by hypoxia) of an endothelium-derived vasoconstrictor, or (3) endothelium-dependent vasoconstriction. Our findings suggest that HPV is both triggered and maintained by cADPR in the rat lung in situ.
Circulation Research - Tập 89 Số 1 - Trang 77-83 - 2001
Cyclic ADP-Ribose Does Not Regulate Sarcoplasmic Reticulum Ca <sup>2+</sup> Release in Intact Cardiac Myocytes
Cyclic ADP-ribose (cADPR), an intracellular second messenger known to mobilize Ca
2+
in sea urchin eggs, has been implicated in modulating Ca
2+
release in a variety of mammalian tissues. On the basis of studies of isolated cardiac sarcoplasmic reticulum (SR) vesicles and single SR Ca
2+
release channels, cADPR has also been proposed to be a modulator of SR Ca
2+
release in heart. In the present study, we directly examined the ability of cADPR to trigger SR Ca
2+
release and to modulate Ca
2+
-induced Ca
2+
release (CICR) in intact rat ventricular myocytes. Voltage-clamped myocytes were dialyzed with up to 100 μmol/L caged cADPR and 0.6 μmol/L calmodulin along with the Ca
2+
-sensitive dye fluo 3. A step increase in the cADPR concentration induced by flash photolysis of caged cADPR neither directly triggered SR Ca
2+
release nor modulated CICR in intact myocytes. In contrast, under similar conditions, extracellular application of caffeine (1 to 2.5 mmol/L) onto myocytes produced both effects. Under equivalent conditions, flash photolysis of caged cADPR-loaded sea urchin eggs resulted in large Ca
2+
transients. Further, the sustained presence of high cytosolic concentrations of either cADPR or its antagonist, 8-amino-cADPR, was ineffective in altering normal CICR in myocytes. These findings indicate that cADPR does not regulate SR Ca
2+
release in intact cardiac myocytes.
Circulation Research - Tập 79 Số 1 - Trang 147-151 - 1996
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