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Joshua I Goldhaber - One of the best experts on this subject based on the ideXlab platform.

  • Acute Genetic Ablation of Cardiac Sodium/Calcium Exchange in Adult Mice: Implications for Cardiomyocyte Calcium Regulation, Cardioprotection, and Arrhythmia
    'Ovid Technologies (Wolters Kluwer Health)', 2021
    Co-Authors: Sabine Lotteau, Rui Zhang, Kenneth D Philipson, Adina Hazan, Christina Grabar, Devina Gonzalez, Stephan Aynaszyan, Michela Ottolia, Joshua I Goldhaber
    Abstract:

    Background Sodium‐Calcium (Ca2+) Exchanger isoform 1 (NCX1) is the dominant Ca2+ efflux mechanism in cardiomyocytes and is critical to maintaining Ca2+ homeostasis during excitation‐contraction coupling. NCX1 activity has been implicated in the pathogenesis of cardiovascular diseases, but a lack of specific NCX1 blockers complicates experimental interpretation. Our aim was to develop a tamoxifen‐inducible NCX1 knockout (KO) mouse to investigate compensatory adaptations of acute ablation of NCX1 on excitation‐contraction coupling and intracellular Ca2+ regulation, and to examine whether acute KO of NCX1 confers resistance to triggered arrhythmia and ischemia/reperfusion injury. Methods and Results We used the α‐myosin heavy chain promoter (Myh6)‐MerCreMer promoter to create a tamoxifen‐inducible cardiac‐specific NCX1 KO mouse. Within 1 week of tamoxifen injection, NCX1 protein expression and current were dramatically reduced. Diastolic Ca2+ increased despite adaptive reductions in Ca2+ current and action potential duration and compensatory increases in excitation‐contraction coupling gain, sarcoplasmic reticulum Ca2+ ATPase 2 and plasma membrane Ca2+ ATPase. As these adaptations progressed over 4 weeks, diastolic Ca2+ normalized and SR Ca2+ load increased. Left ventricular function remained normal, but mild fibrosis and hypertrophy developed. Transcriptomics revealed modification of cardiovascular‐related gene networks including cell growth and fibrosis. NCX1 KO reduced spontaneous action potentials triggered by delayed afterdepolarizations and reduced scar size in response to ischemia/reperfusion. Conclusions Tamoxifen‐inducible NCX1 KO mice adapt to acute genetic ablation of NCX1 by reducing Ca2+ influx, increasing alternative Ca2+ efflux pathways, and increasing excitation‐contraction coupling gain to maintain contractility at the cost of mild Ca2+‐activated hypertrophy and fibrosis and decreased survival. Nevertheless, KO myocytes are protected against spontaneous action potentials and ischemia/reperfusion injury

  • burst pacemaker activity of the sinoatrial node in Sodium Calcium Exchanger knockout mice
    Proceedings of the National Academy of Sciences of the United States of America, 2015
    Co-Authors: Angelo G Torrente, Scott T Lamp, Rui Zhang, Audrey Zaini, Jorge F Giani, Jeanney Kang, Kenneth D Philipson, Joshua I Goldhaber
    Abstract:

    In sinoatrial node (SAN) cells, electrogenic Sodium–Calcium Exchange (NCX) is the dominant Calcium (Ca) efflux mechanism. However, the role of NCX in the generation of SAN automaticity is controversial. To investigate the contribution of NCX to pacemaking in the SAN, we performed optical voltage mapping and high-speed 2D laser scanning confocal microscopy (LSCM) of Ca dynamics in an ex vivo intact SAN/atrial tissue preparation from atrial-specific NCX knockout (KO) mice. These mice lack P waves on electrocardiograms, and isolated NCX KO SAN cells are quiescent. Voltage mapping revealed disorganized and arrhythmic depolarizations within the NCX KO SAN that failed to propagate into the atria. LSCM revealed intermittent bursts of Ca transients. Bursts were accompanied by rising diastolic Ca, culminating in long pauses dominated by Ca waves. The L-type Ca channel agonist BayK8644 reduced the rate of Ca transients and inhibited burst generation in the NCX KO SAN whereas the Ca buffer 1,2-Bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (acetoxymethyl ester) (BAPTA AM) did the opposite. These results suggest that cellular Ca accumulation hinders spontaneous depolarization in the NCX KO SAN, possibly by inhibiting L-type Ca currents. The funny current (If) blocker ivabradine also suppressed NCX KO SAN automaticity. We conclude that pacemaker activity is present in the NCX KO SAN, generated by a mechanism that depends upon If. However, the absence of NCX-mediated depolarization in combination with impaired Ca efflux results in intermittent bursts of pacemaker activity, reminiscent of human sinus node dysfunction and “tachy-brady” syndrome.

  • na ca Exchange and contraction of the heart
    Journal of Molecular and Cellular Cardiology, 2013
    Co-Authors: Michela Ottolia, John H B Bridge, Kenneth D Philipson, Natalia S Torres, Joshua I Goldhaber
    Abstract:

    Sodium-Calcium Exchange (NCX) is the major Calcium (Ca) efflux mechanism of ventricular cardiomyocytes. Consequently the Exchanger plays a critical role in the regulation of cellular Ca content and hence contractility. Reductions in Ca efflux by the Exchanger, such as those produced by elevated intracellular Sodium (Na) in response to cardiac glycosides, raise sarcoplasmic reticulum (SR) Ca stores. The result is an increased Ca transient and cardiac contractility. Enhanced Ca efflux activity by the Exchanger, for example during heart failure, may reduce diadic cleft Ca and excitation-contraction (EC) coupling gain. This aggravates the impaired contractility associated with SR Ca ATPase dysfunction and reduced SR Ca load in failing heart muscle. Recent data from our laboratories indicate that NCX can also impact the efficiency of EC coupling and contractility independent of SR Ca load through diadic cleft priming with Ca during the upstroke of the action potential. This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes".

  • cardiac Sodium Calcium Exchange and efficient excitation contraction coupling implications for heart disease
    Advances in Experimental Medicine and Biology, 2013
    Co-Authors: Joshua I Goldhaber, Kenneth D Philipson
    Abstract:

    Cardiovascular disease is a leading cause of death worldwide, with ischemic heart disease alone accounting for >12% of all deaths, more than HIV/AIDS, tuberculosis, lung, and breast cancer combined. Heart disease has been the leading cause of death in the United States for the past 85 years and is a major cause of disability and health-care expenditures. The cardiac conditions most likely to result in death include heart failure and arrhythmias, both a consequence of ischemic coronary disease and myocardial infarction, though chronic hypertension and valvular diseases are also important causes of heart failure. Sodium-Calcium Exchange (NCX) is the dominant Calcium (Ca2+) efflux mechanism in cardiac cells. Using ventricular-specific NCX knockout mice, we have found that NCX is also an essential regulator of cardiac contractility independent of sarcoplasmic reticulum Ca2+ load. During the upstroke of the action potential, Sodium (Na+) ions enter the diadic cleft space between the sarcolemma and the sarcoplasmic reticulum. The rise in cleft Na+, in conjunction with depolarization, causes NCX to transiently reverse. Ca2+ entry by this mechanism then “primes” the diadic cleft so that subsequent Ca2+ entry through Ca2+ channels can more efficiently trigger Ca2+ release from the sarcoplasmic reticulum. In NCX knockout mice, this mechanism is inoperative (Na+ current has no effect on the Ca2+ transient), and excitation-contraction coupling relies upon the elevated diadic cleft Ca2+ that arises from the slow extrusion of cytoplasmic Ca2+ by the ATP-dependent sarcolemmal Ca2+ pump. Thus, our data support the conclusion that NCX is an important regulator of cardiac contractility. These findings suggest that manipulation of NCX may be beneficial in the treatment of heart failure.

  • local regulation of the threshold for Calcium sparks in rat ventricular myocytes role of Sodium Calcium Exchange
    The Journal of Physiology, 1999
    Co-Authors: Joshua I Goldhaber, Scott T Lamp, Donald O Walter, A F Garfinkel, Gary H Fukumoto, James N Weiss
    Abstract:

    1. To determine whether Na+-Ca2+ Exchange modulates Ca2+ sparks, we studied enzymatically isolated patch clamped rat ventricular myocytes loaded with the Ca2+-sensitive indicator fluo-3, using confocal microscopy at 20-22 C. Two-dimensional images of Ca2+ sparks were recorded at 240 Hz using a laser scanning confocal microscope, allowing observation of a large area of the cell (820 microm2) at one time. 2. At a holding potential of -75 mV, spontaneous sparks were infrequent. Removal of extracellular Na+ for 520 ms, which in the absence of pipette Na+ should block Na+-Ca2+ Exchange bidirectionally, was associated with a fourfold increase in spark frequency, without a significant change in cytoplasmic [Ca2+], sarcoplasmic reticulum (SR) Ca2+ content, or spark intensity, size or time course. 3. These findings are consistent with a model of excitation-contraction coupling in which Na+-Ca2+ Exchange locally regulates the resting Ca2+ concentration in the diadic cleft (T-tubule-SR junction), thereby modulating the threshold for triggering Ca2+ sparks.

Donald M Bers - One of the best experts on this subject based on the ideXlab platform.

  • arrhythmogenesis and contractile dysfunction in heart failure roles of Sodium Calcium Exchange inward rectifier potassium current and residual β adrenergic responsiveness
    Circulation Research, 2001
    Co-Authors: Steven M Pogwizd, Klaus Schlotthauer, Li Li, Weilong Yuan, Donald M Bers
    Abstract:

    Abstract —Ventricular arrhythmias and contractile dysfunction are the main causes of death in human heart failure (HF). In a rabbit HF model reproducing these same aspects of human HF, we demonstrate that a 2-fold functional upregulation of Na+-Ca2+ Exchange (NaCaX) unloads sarcoplasmic reticulum (SR) Ca2+ stores, reducing Ca2+ transients and contractile function. Whereas β-adrenergic receptors (β-ARs) are progressively downregulated in HF, residual β-AR responsiveness at this critical HF stage allows SR Ca2+ load to increase, causing spontaneous SR Ca2+ release and transient inward current carried by NaCaX. A given Ca2+ release produces greater arrhythmogenic inward current in HF (as a result of NaCaX upregulation), and ≈50% less Ca2+ release is required to trigger an action potential in HF. The inward rectifier potassium current ( I K1) is reduced by 49% in HF, and this allows greater depolarization for a given NaCaX current. Partially blocking I K1 in control cells with barium mimics the greater depolarization for a given current injection seen in HF. Thus, we present data to support a novel paradigm in which changes in NaCaX and I K1, and residual β-AR responsiveness, conspire to greatly increase the propensity for triggered arrhythmias in HF. In addition, NaCaX upregulation appears to be a critical link between contractile dysfunction and arrhythmogenesis.

  • arrhythmogenesis and contractile dysfunction in heart failure roles of Sodium Calcium Exchange inward rectifier potassium current and residual β adrenergic responsiveness
    Circulation Research, 2001
    Co-Authors: Steven M Pogwizd, Klaus Schlotthauer, Weilong Yuan, Donald M Bers
    Abstract:

    Ventricular arrhythmias and contractile dysfunction are the main causes of death in human heart failure (HF). In a rabbit HF model reproducing these same aspects of human HF, we demonstrate that a 2-fold functional upregulation of Na(+)-Ca(2+) Exchange (NaCaX) unloads sarcoplasmic reticulum (SR) Ca(2+) stores, reducing Ca(2+) transients and contractile function. Whereas beta-adrenergic receptors (beta-ARs) are progressively downregulated in HF, residual beta-AR responsiveness at this critical HF stage allows SR Ca(2+) load to increase, causing spontaneous SR Ca(2+) release and transient inward current carried by NaCaX. A given Ca(2+) release produces greater arrhythmogenic inward current in HF (as a result of NaCaX upregulation), and approximately 50% less Ca(2+) release is required to trigger an action potential in HF. The inward rectifier potassium current (I(K1)) is reduced by 49% in HF, and this allows greater depolarization for a given NaCaX current. Partially blocking I(K1) in control cells with barium mimics the greater depolarization for a given current injection seen in HF. Thus, we present data to support a novel paradigm in which changes in NaCaX and I(K1), and residual beta-AR responsiveness, conspire to greatly increase the propensity for triggered arrhythmias in HF. In addition, NaCaX upregulation appears to be a critical link between contractile dysfunction and arrhythmogenesis.

  • potentiation of fractional sarcoplasmic reticulum Calcium release by total and free intra sarcoplasmic reticulum Calcium concentration
    Biophysical Journal, 2000
    Co-Authors: Thomas R Shannon, Kenneth S Ginsburg, Donald M Bers
    Abstract:

    Our aim was to measure the influence of sarcoplasmic reticulum (SR) Calcium content ([Ca](SRT)) and free SR [Ca] ([Ca](SR)) on the fraction of SR Calcium released during voltage clamp steps in isolated rabbit ventricular myocytes. [Ca](SRT), as measured by caffeine application, was progressively increased by conditioning pulses. Sodium was absent in both the intracellular and in the extracellular solutions to block Sodium/Calcium Exchange. Total cytosolic Calcium flux during the transient was inferred from I(Ca), [Ca](SRT), [Ca](i), and cellular buffering characteristics. Fluxes via the Calcium current (I(Ca)), the SR Calcium pump, and passive leak from the SR were evaluated to determine SR Calcium release flux (J(rel)). Excitation-contraction (EC) coupling was characterized with respect to both gain (integral J(rel)/integral I(Ca)) and fractional SR Calcium release. Both parameters were virtually zero for a small, but measurable [Ca](SRT). Gain and fractional SR Calcium release increased steeply and nonlinearly with both [Ca](SRT) and [Ca](SR). We conclude that potentiation of EC coupling can be correlated with both [Ca](SRT) and [Ca](SR). While fractional SR Calcium release was not linearly dependent upon [Ca](SR), intra-SR Calcium may play a crucial role in regulating the SR Calcium release process.

Daoyan Liu - One of the best experts on this subject based on the ideXlab platform.

  • deficiency of pkd2l1 trpp3 exacerbates pathological cardiac hypertrophy by augmenting ncx1 mediated mitochondrial Calcium overload
    Cell Reports, 2018
    Co-Authors: Yuanting Cui, Xing Wei, Peng Gao, Hexuan Zhang, Xiao Wei, Fang Sun, Zhencheng Yan, Hongting Zheng, Gangyi Yang, Daoyan Liu
    Abstract:

    Summary High salt intake is one independent risk factor for cardiac hypertrophy. Polycystic kidney disease 2-like 1 (PKD2L1, also called TRPP3) acts as a sour sensor in taste cells, and its possible role in the cardiovascular system is unknown. Here, we report that knockout of PKD2L1 exacerbated high-salt diet (HSD)-induced cardiac hypertrophy and fibrosis, accompanied by cardiac dysfunction and reduced cardiac mitochondrial oxidative phosphorylation and enzyme activity. Furthermore, knockdown of PKD2L1 led to more serious mitochondrial Ca2+ overload and reduced Ca2+ uptake in cardiomyocytes on high salt loading. Mechanistically, PKD2L1 deficiency increased p300-mediated acetylation of histone 3 lysine 27 on the promoter of Sodium/Calcium Exchange 1 (NCX1) by repressing AMP-activated protein kinase (AMPK) activity, resulting in NCX1 overexpression and mitochondrial Ca2+ overload. These results reveal an inhibitory effect of PKD2L1 on cardiac hypertrophy and provide a mechanistic insight into the link between mitochondrial Ca2+ homeostasis and cardiac hypertrophy.

Yuanting Cui - One of the best experts on this subject based on the ideXlab platform.

  • deficiency of pkd2l1 trpp3 exacerbates pathological cardiac hypertrophy by augmenting ncx1 mediated mitochondrial Calcium overload
    Cell Reports, 2018
    Co-Authors: Yuanting Cui, Xing Wei, Peng Gao, Hexuan Zhang, Xiao Wei, Fang Sun, Zhencheng Yan, Hongting Zheng, Gangyi Yang, Daoyan Liu
    Abstract:

    Summary High salt intake is one independent risk factor for cardiac hypertrophy. Polycystic kidney disease 2-like 1 (PKD2L1, also called TRPP3) acts as a sour sensor in taste cells, and its possible role in the cardiovascular system is unknown. Here, we report that knockout of PKD2L1 exacerbated high-salt diet (HSD)-induced cardiac hypertrophy and fibrosis, accompanied by cardiac dysfunction and reduced cardiac mitochondrial oxidative phosphorylation and enzyme activity. Furthermore, knockdown of PKD2L1 led to more serious mitochondrial Ca2+ overload and reduced Ca2+ uptake in cardiomyocytes on high salt loading. Mechanistically, PKD2L1 deficiency increased p300-mediated acetylation of histone 3 lysine 27 on the promoter of Sodium/Calcium Exchange 1 (NCX1) by repressing AMP-activated protein kinase (AMPK) activity, resulting in NCX1 overexpression and mitochondrial Ca2+ overload. These results reveal an inhibitory effect of PKD2L1 on cardiac hypertrophy and provide a mechanistic insight into the link between mitochondrial Ca2+ homeostasis and cardiac hypertrophy.

  • Deficiency of PKD2L1 (TRPP3) Exacerbates Pathological Cardiac Hypertrophy by Augmenting NCX1-Mediated Mitochondrial Calcium Overload
    Elsevier, 2018
    Co-Authors: Yuanting Cui, Xing Wei, Peng Gao, Hexuan Zhang, Xiao Wei, Fang Sun, Zhencheng Yan, Hongting Zheng
    Abstract:

    Summary: High salt intake is one independent risk factor for cardiac hypertrophy. Polycystic kidney disease 2-like 1 (PKD2L1, also called TRPP3) acts as a sour sensor in taste cells, and its possible role in the cardiovascular system is unknown. Here, we report that knockout of PKD2L1 exacerbated high-salt diet (HSD)-induced cardiac hypertrophy and fibrosis, accompanied by cardiac dysfunction and reduced cardiac mitochondrial oxidative phosphorylation and enzyme activity. Furthermore, knockdown of PKD2L1 led to more serious mitochondrial Ca2+ overload and reduced Ca2+ uptake in cardiomyocytes on high salt loading. Mechanistically, PKD2L1 deficiency increased p300-mediated acetylation of histone 3 lysine 27 on the promoter of Sodium/Calcium Exchange 1 (NCX1) by repressing AMP-activated protein kinase (AMPK) activity, resulting in NCX1 overexpression and mitochondrial Ca2+ overload. These results reveal an inhibitory effect of PKD2L1 on cardiac hypertrophy and provide a mechanistic insight into the link between mitochondrial Ca2+ homeostasis and cardiac hypertrophy. : Lu et al. reveal a role of a mitochondria-localized TRPP member, PKD2L1, in high salt-induced cardiac hypertrophy. PKD2L1 knockout leads to overexpression of NCX1 through increasing the acetylation level of histone 3 lysine 27 on NCX1 promoter and thus exacerbates mitochondrial Calcium overload by activating the reverse mode of NCX1 in cardiomyocytes. Keywords: high-salt diet, cardiac hypertrophy, PKD2L1, mitochondria, NCX

Allan J. Levi - One of the best experts on this subject based on the ideXlab platform.

  • relation between reverse Sodium Calcium Exchange and sarcoplasmic reticulum Calcium release in guinea pig ventricular cells
    Circulation Research, 1994
    Co-Authors: O Kohomoto, Allan J. Levi, John H B Bridge
    Abstract:

    Exchange-inhibitory peptide (XIP) can inhibit Sodium-Calcium Exchange without inhibiting L-type Calcium current (ICa). We therefore used this compound to test the hypothesis that reverse Sodium-Calcium Exchange can trigger contraction in guinea pig ventricular myocytes. When cells were dialyzed with 20 mmol/L Sodium, rapid blockade of ICa with nifedipine had little effect on cell shortening. However, if reverse Exchange was inhibited by first dialyzing the cells with XIP, blockade of ICa largely inhibited cell shortening. In cells dialyzed with 10 mmol/L Sodium, about 51% of the maximum cell shortening remained after ICa was blocked. When both ICa and reverse Exchange were significantly inhibited with nifedipine and XIP, only 24% of the cell shortening remained; ie, 27% was XIP inhibitable. Cells dialyzed with solutions deficient in Sodium exhibited contractions that were largely dependent on ICa (ie, not XIP inhibitable). If the sarcoplasmic reticulum (SR) was disabled with ryanodine and thapsigargin, reverse Exchange could not cause contraction. We therefore conclude that with intact SR, reverse Sodium-Calcium Exchange activates contraction by triggering Calcium release from the SR in cells dialyzed with either 10 or 20 mmol/L Sodium. A scrambled sequence of XIP, sXIP, caused no measurable effect on contraction.

  • a role for Sodium Calcium Exchange in the action potential shortening caused by strophanthidin in guinea pig ventricular myocytes
    Cardiovascular Research, 1993
    Co-Authors: Allan J. Levi
    Abstract:

    Objective: The aim was to investigate the nature of the membrane currents which underlie the shortening of the action potential in guinea pig cardiac myocytes upon exposure to the digitalis analogue strophanthidin. Methods: Ventricular myocytes were isolated enzymatically from the guinea pig heart and impaled with conventional microelectrodes to measure action potentials. Cells were voltage clamped and the change in membrane current upon strophanthidin exposure was recorded. Contractile activity was assessed optically as cell shortening. Results: Strophanthidin caused an initial lengthening followed by a progressive shortening of the action potential. The initial lengthening was due to an inhibition of outward Na/K pump current caused by strophanthidin. The subsequent action potential shortening was associated with the progressive activation of a membrane current that reversed at −54.5(SD 7.5) mV, n=8. Since this current was outward over the potential range of the action potential plateau, it participated in causing the action potential shortening with strophanthidin. This component of membrane current was not sensitive to potassium channel blockers, but it was blocked by removing external Ca and applying 5 mM nickel externally. Removal of external Ca inhibits outward current generated by the Ca entry/Na extrusion mode of the Na/Ca Exchange, whereas nickel is known to block the Na/Ca Exchange. Conclusions: The voltage dependence of the membrane current associated with progressive action potential shortening, and its sensitivity to external Ca and nickel, suggest that it is carried on the Na/Ca Exchange. It is proposed that the Na/Ca Exchange generates this membrane current in response to the combined rise of intracellular Sodium and Calcium that occurs with strophanthidin. Theoretical calculations simulating the effect of a combined rise of intracellular Sodium and Calcium on Na/Ca Exchange predict closely the reversal potential and characteristics of the experimentally measured current. The results of this study suggest that a membrane current generated by the Na/Ca Exchange makes an important contribution to the action potential shortening that occurs with digitalis compounds. Cardiovascular Research 1993; 27 :471-481