Robert A Rose

Dalhousie University, Halifax, Nova Scotia, Canada

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Publications (28)167.2 Total impact

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    ABSTRACT: Previous studies have shown that ventricular myocytes from female rats have smaller contractions and Ca(2+) transients than that of males. As cardiac contraction is regulated by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway, we hypothesized that sex differences in cAMP contribute to differences in Ca(2+) handling. Ca(2+) transients (fura-2) and ionic currents were measured simultaneously (37°C, 2Hz) in ventricular myocytes from adult male and female C57BL/6 mice. Under basal conditions, diastolic Ca(2+), sarcoplasmic reticulum (SR) Ca(2+) stores, and L-type Ca(2+) current did not differ between the sexes. However, female myocytes had smaller Ca(2+) transients (26% smaller), Ca(2+) sparks (6% smaller), and excitation-contraction coupling gain in comparison to males (23% smaller). Interestingly, basal levels of intracellular cAMP were lower in female myocytes (0.7±0.1 vs. 1.7±0.2fmol/μg protein; p<0.001). Importantly, PKA inhibition (2μM H-89) eliminated male-female differences in Ca(2+) transients and gain, as well as Ca(2+) spark amplitude. Western blots showed that PKA inhibition also reduced the ratio of phospho:total RyR2 in male hearts, but not in female hearts. Stimulation of cAMP production with 10μM forskolin abolished sex differences in cAMP levels, as well as differences in Ca(2+) transients, sparks, and gain. To determine if the breakdown of cAMP differed between the sexes, phosphodiesterase (PDE) mRNA levels were measured. PDE3 expression was similar in males and females, but PDE4B expression was higher in female ventricles. The inhibition of cAMP breakdown by PDE4 (10μM rolipram) abolished differences in Ca(2+) transients and gain. These findings suggest that female myocytes have lower levels of basal cAMP, due, in part, to higher expression of PDE4B. Lower cAMP levels in females may attenuate PKA phosphorylation of Ca(2+) handling proteins in females, and may limit positive inotropic responses to stimulation of the cAMP/PKA pathway in female hearts.
    Journal of Molecular and Cellular Cardiology 07/2014; · 5.15 Impact Factor
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    ABSTRACT: Natriuretic peptides, including BNP and CNP, are powerful regulators of the cardiovascular system; however, their electrophysiological effects in the heart, particularly in the sinoatrial node (SAN), are incompletely understood. We have used high resolution optical mapping to measure the effects of BNP and CNP, and the roles of natriuretic peptide receptors (NPR-A, NPR-B and NPR-C), on electrical conduction within the SAN and atrial myocardium. In basal conditions BNP and CNP (50-500 nM) increased conduction velocity (CV) within the SAN by ~30% at the high dose and shifted the initial exit site superiorly. These effects sped conduction from the SAN to the surrounding atrial myocardium and were mediated by the NPR-A and NPR-B receptors. In the presence of isoproterenol (ISO; 1 μM) the NPR-C receptor made a major contribution to the effects of BNP and CNP in the heart. In these conditions BNP, CNP and the NPR-C agonist cANF each decreased SAN CV and shifted the initial exit site inferiorly. The effects of cANF (30% reduction) were larger than BNP or CNP (~15% reduction) indicating that BNP and CNP activate multiple NPRs. In support of this, the inhibitory effects of BNP were absent in NPR-C knockout mice, where BNP instead elicited a further increase (~25%) in CV. Measurements in externally paced atrial preparations demonstrate that the effects of NPs on CV are partially independent of changes in cycle length. These data provide detailed novel insight into the complex effects of natriuretic peptides and their receptors on electrical conduction in the heart.
    The Journal of Physiology 12/2013; · 4.38 Impact Factor
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    ABSTRACT: We previously quantified frailty in aged mice with frailty index (FI) that used specialized equipment to measure health parameters. Here we developed a simplified, noninvasive method to quantify frailty through clinical assessment of C57BL/6J mice (5-28 months) and compared the relationship between FI scores and age in mice and humans. FIs calculated with the original performance-based eight-item FI increased from 0.06±0.01 at 5 months to 0.36±0.06 at 19 months and 0.38±0.04 at 28 months (n = 14). By contrast, the increase was graded with a 31-item clinical FI (0.02±0.005 at 5 months; 0.12±0.008 at 19 months; 0.33±0.02 at 28 months; n = 14). FI scores calculated from 70 self-report items from the first wave of the Survey of Health, Ageing and Retirement in Europe were plotted as function of age (n = 30,025 people). The exponential relationship between FI scores and age (normalized to 90% mortality) was similar in mice and humans for the clinical FI but not the eight-item FI. This noninvasive FI based on clinical measures can be used in longitudinal studies to quantify frailty in mice. Unlike the performance-based eight-item mouse FI, the clinical FI exhibits key features of the FI established for use in humans.
    The Journals of Gerontology Series A Biological Sciences and Medical Sciences 09/2013; · 4.31 Impact Factor
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    ABSTRACT: Aged hearts are particularly vulnerable to ischemia-reperfusion injury. Our objective was to determine if del Nido cardioplegia, which contains lidocaine, less blood, and less calcium than our standard cardioplegia, provides superior protection for aged hearts. We also sought to determine if the lidocaine in del Nido cardioplegia is adequate to prevent Na(+) influx via the window current. Sodium channel kinetics were measured in rat cardiomyocytes with and without lidocaine. Recovery after 60 minutes of cardioplegic arrest was assessed in isolated working senescent rat hearts. Del Nido cardioplegia was delivered as a single dose (n = 8) because it is used clinically, and standard cardioplegia was delivered as an induction dose with re-dosing every 20 minutes (n = 8). After 20 minutes of reperfusion, hearts were switched to working mode for 60 minutes. Flows were indexed to ventricular dry weight. Troponin release was assayed. Sodium channel kinetics indicated that the lidocaine concentration in del Nido cardioplegia minimizes the potential for Na+ influx via the window current. Spontaneous contractions occurred in fewer hearts arrested with del Nido cardioplegia (88% vs 13%; P = .01), and troponin release was reduced (0.24 vs 0.89 ng/mL; P = .017). Cardiac output was approximately 90% of baseline in the del Nido group compared with approximately 50% in the standard group (173 ± 14 vs 86 ± 22 mL · min(-1) · g(-1); P = .0008). Stroke work was higher in the del Nido group (93 ± 6 vs 41 ± 10 mL · mm Hg · g(-1); P = .0002). Del Nido cardioplegia prevents spontaneous contractions during arrest, reduces troponin release, and results in superior myocardial function in isolated aged hearts. Del Nido cardioplegia has the potential to provide superior myocardial protection for older patients undergoing cardiac surgery.
    The Journal of thoracic and cardiovascular surgery 08/2013; · 3.41 Impact Factor
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    ABSTRACT: Abstract The mechanisms by which statins are beneficial are incompletely understood. While the lowering of low-density lipoprotein concentration is associated with regression of atherosclerosis, the observed benefit of statin therapy begins within months after its initiation, making regression an unlikely cause. Although LDL-C lowering is the main mechanism by which statin therapy reduces cardiovascular events, evidence suggests that at least some of the beneficial actions of statins may be mediated by their pleiotropic effects. Thus, statins may modulate the function of cardiovascular cells and key signalling proteins, including small G-proteins, to ultimately exert their pleiotropic effects. Sphingosine-1-phosphate (S1P) is a naturally occurring bioactive lysophospholipid that regulates diverse physiological functions in a variety of different organ systems. Within the cardiovascular system, S1P mediates cardioprotection following ischemia/reperfusion injury, anti-inflammatory response, improvement of endothelial function, increased mobilization and differentiation of endothelial progenitor cells, inhibition of oxidation, and anti-atherogenic and anti-thrombotic actions. Early evidence suggests that the pleiotropic effects of statins may be related to an increase in S1P signalling. This review focuses on S1P signalling as the potential mechanism underlying the pleiotropic effects of statins. An improved understanding of this mechanism may be vital for establishing the clinical relevance of statins and their importance in the treatment and prevention of coronary artery disease. Key points Several studies have demonstrated a benefit from lowering serum LDL-C with statins in patients with and without clinical evidence of CAD. These may be mediated by the pleiotropic effects of statins-the mechanisms of which are incompletely understood. Early evidence suggests that statins may increase S1P signalling pathways through upregulation of the expression of S1P receptors and an increase in plasma levels of S1P to ultimately exert their pleiotropic effects. Future clinical trials and basic science research aimed at the underlying mechanisms of the pleiotropic effects of statins should enlighten us to their relative clinical relevance and importance.
    Critical Reviews in Clinical Laboratory Sciences 05/2013; 50(3):79-89. · 3.78 Impact Factor
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    ABSTRACT: This study determined whether deficiency of ovarian estrogen starting very early in life promoted age-associated Ca(2+) dysregulation and contractile dysfunction in isolated ventricular myocytes. Myocytes were isolated from anesthetized C57BL/6 female mice. Animals received an ovariectomy or sham-operation at one month and were aged to ~24 months. Excitation-contraction coupling parameters were compared in fura-2 loaded myocytes (37°C). While Ca(2+) transients were larger and faster in field-stimulated myocytes from ovariectomized mice, ovariectomy had no effect on peak fractional shortening. Similarly, ovariectomy had no effect on fractional shortening measured in vivo by echocardiography (values were 60.5 ± 2.9 vs. 60.3 ± 2.5% in sham and ovariectomized, respectively; n=5 mice/group). Ovariectomy did decrease myofilament Ca(2+) sensitivity, as evidenced by a 26% increase in the Ca(2+) required to activate actomyosin MgATPase in ovariectomized hearts. Larger Ca(2+) transients were attributable to a 48% increase in peak Ca(2+) current, along with an increase in the amplitude, width and frequency of Ca(2+) sparks measured in fluo-4 loaded myocytes. These changes in Ca(2+) handling were not due to increased expression of Ca(2+) channels (Cav1.2), sarcoplasmic reticulum Ca(2+) ATPase (SERCA2) or Na(+)-Ca(2+) exchanger in ovariectomized hearts. However, ovariectomy increased sarcoplasmic reticulum Ca(2+) stores by ~90% and promoted spontaneous Ca(2+) release from the sarcoplasmic reticulum when compared to sham controls. These observations demonstrate that long-term ovariectomy promotes intracellular Ca(2+) dysregulation, reduces myofilament Ca(2+) sensitivity and increases spontaneous Ca(2+) release in the aging female heart.
    PLoS ONE 01/2013; 8(9):e74719. · 3.73 Impact Factor
  • Circulation 10/2012; 126(17):2039-41. · 15.20 Impact Factor
  • John Azer, Rui Hua, Kimberly Vella, Robert A Rose
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    ABSTRACT: Natriuretic peptides, including BNP and CNP, elicit their effects via two guanylyl cyclase-linked receptors denoted NPR-A and NPR-B as well as a third receptor, NPR-C. The relative contributions of these receptors to the overall effects of NPs on heart rate (HR) and sinoatrial node (SAN) function are very poorly understood. The effects of BNP and CNP (10-500nM) on HR and SAN myocyte spontaneous action potential (AP) firing were studied using wildtype mice and mice lacking functional NPR-C receptors (NPR-C(-/-)). In basal conditions and 10nM doses of the β-adrenergic receptor (β-AR) agonist isoproterenol (ISO) BNP and CNP increased HR and AP firing in SAN myocytes. The NPR-C selective agonist cANF (10-500nM) had no effects in basal conditions, but decreased HR and SAN AP frequency in the presence of ISO. These effects of cANF were completely absent in NPR-C(-/-) mice. Strikingly, in the presence of 1μM doses of ISO, BNP and CNP switched to causing decreases in HR and SAN AP frequency. These decreases were not as large as those elicited by cANF and were absent in NPR-C(-/-) hearts, where BNP instead elicited a further increase in HR. Inhibition of NPR-A with A71915, in the presence of 1μM ISO, enabled BNP to signal exclusively through NPR-C and to decrease HR as effectively as cANF. Together these data demonstrate that BNP and CNP affect HR and SAN function by activating multiple receptor subtypes. NPR-A/B mediate increases in HR and SAN function, but these effects are opposed by NPR-C, which plays an increasingly important signaling role in the presence of β-AR stimulation.
    Journal of Molecular and Cellular Cardiology 08/2012; 53(5):715-24. · 5.15 Impact Factor
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    ABSTRACT: Natriuretic peptides (NPs) are best known for their ability to regulate blood vessel tone and kidney function whereas their electrophysiological effects on the heart are less clear. Here, we measured the effects of BNP and CNP on sinoatrial node (SAN) and atrial electrophysiology in isolated hearts as well as isolated SAN and right atrial myocytes from mice. BNP and CNP dose-dependently increased heart rate and conduction through the heart as indicated by reductions in R-R interval, P wave duration and P-R interval on ECGs. In conjunction with these ECG changes BNP and CNP (100 nM) increased spontaneous action potential frequency in isolated SAN myocytes by increasing L-type Ca(2+) current (I(Ca,L)) and the hyperpolarization-activated current (I(f)). BNP had no effect on right atrial myocyte APs in basal conditions; however, in the presence of isoproterenol (10nM), BNP increased atrial AP duration and I(Ca,L). Quantitative gene expression and immunocytochemistry data show that all three NP receptors (NPR-A, NPR-B and NPR-C) are expressed in the SAN and atrium. The effects of BNP and CNP on SAN and right atrial myocytes were maintained in mutant mice lacking functional NPR-C receptors and blocked by the NPR-A antagonist A71915 indicating that BNP and CNP function through their guanylyl cyclase-linked receptors. Our data also show that the effects of BNP and CNP are completely absent in the presence of the phosphodiesterase 3 inhibitor milrinone. Based on these data we conclude that NPs can increase heart rate and electrical conduction by activating the guanylyl cyclase-linked NPR-A and NPR-B receptors and inhibiting PDE3 activity.
    Journal of Molecular and Cellular Cardiology 02/2012; 52(5):1122-34. · 5.15 Impact Factor
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    ABSTRACT: Phosphodiesterases (PDEs) are critical regulators of cyclic nucleotides in the heart. In ventricular myocytes, the L-type Ca(2+) current (I(Ca,L)) is a major target of regulation by PDEs, particularly members of the PDE2, PDE3 and PDE4 families. Conversely, much less is known about the roles of PDE2, PDE3 and PDE4 in the regulation of action potential (AP) properties and I(Ca,L) in the sinoatrial node (SAN) and the atrial myocardium, especially in mice. Thus, the purpose of our study was to measure the effects of global PDE inhibition with Isobutyl-1-methylxanthine (IBMX) and selective inhibitors of PDE2, PDE3 and PDE4 on AP properties in isolated mouse SAN and right atrial myocytes. We also measured the effects of these inhibitors on I(Ca,L) in SAN and atrial myocytes in comparison to ventricular myocytes. Our data demonstrate that IBMX markedly increases spontaneous AP frequency in SAN myocytes and AP duration in atrial myocytes. Spontaneous AP firing in SAN myocytes was also increased by the PDE2 inhibitor erythro-9-[2-hydroxy-3-nonyl] adenine (EHNA), the PDE3 inhibitor milrinone (Mil) and the PDE4 inhibitor rolipram (Rol). In contrast, atrial AP duration was increased by EHNA and Rol, but not by Mil. IBMX also potently, and similarly, increased I(Ca,L) in SAN, atrial and ventricular myocytes; however, important differences emerged in terms of which inhibitors could modulate I(Ca,L) in each myocyte type. Consistent with our AP measurements, EHNA, Mil and Rol each increased I(Ca,L) in SAN myocytes. Also, EHNA and Rol, but not Mil, increased atrial I(Ca,L). In complete contrast, no selective PDE inhibitors increased I(Ca,L) in ventricular myocytes when given alone. Thus, our data show that the effects of selective PDE2, PDE3 and PDE4 inhibitors are distinct in the different regions of the myocardium indicating important differences in how each PDE family constitutively regulates ion channel function in the SAN, atrial and ventricular myocardium.
    PLoS ONE 01/2012; 7(10):e47652. · 3.73 Impact Factor
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    Robert A Rose
    Experimental physiology 11/2011; 96(11):1114-5. · 3.17 Impact Factor
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    ABSTRACT: Rapid electrical conduction in the His-Purkinje system tightly controls spatiotemporal activation of the ventricles. Although recent work has shed much light on the regulation of early specification and morphogenesis of the His-Purkinje system, less is known about how transcriptional regulation establishes impulse conduction properties of the constituent cells. Here we show that Iroquois homeobox gene 3 (Irx3) is critical for efficient conduction in this specialized tissue by antithetically regulating two gap junction-forming connexins (Cxs). Loss of Irx3 resulted in disruption of the rapid coordinated spread of ventricular excitation, reduced levels of Cx40, and ectopic Cx43 expression in the proximal bundle branches. Irx3 directly represses Cx43 transcription and indirectly activates Cx40 transcription. Our results reveal a critical role for Irx3 in the precise regulation of intercellular gap junction coupling and impulse propagation in the heart.
    Proceedings of the National Academy of Sciences 08/2011; 108(33):13576-81. · 9.81 Impact Factor
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    ABSTRACT: Excitation-contraction coupling (ECC) in cardiac myocytes involves triggering of Ca(2+) release from the sarcoplasmic reticulum (SR) by L-type Ca channels, whose activity is strongly influenced by action potential (AP) profile. The contribution of Ca(2+) entry via the Na(+)/Ca(2+) exchanger (NCX) to trigger SR Ca(2+) release during ECC in response to an AP remains uncertain. To isolate the contribution of NCX to SR Ca(2+) release, independent of effects on SR Ca(2+) load, Ca(2+) release was determined by recording Ca(2+) spikes using confocal microscopy on patch-clamped rat ventricular myocytes with [Ca(2+)](i) fixed at 150 nmol/L. In response to AP clamps, normalized Ca(2+) spike amplitudes (ΔF/F (0)) increased sigmoidally and doubled as [Na(+)](i) was elevated from 0 to 20 mmol/L with an EC(50) of ~10 mmol/L. This [Na(+)](i)-dependence was independent of I (Na) as well as SR Ca(2+) load, which was unchanged under our experimental conditions. However, NCX inhibition using either KB-R7943 or XIP reduced ΔF/F (0) amplitude in myocytes with 20 mmol/L [Na(+)](i), but not with 5 mmol/L [Na(+)](i). SR Ca(2+) release was complete before the membrane repolarized to -15 mV, indicating Ca(2+) entry into the dyad (not reduced extrusion) underlies [Na(+)](i)-dependent enhancement of ECC. Because I (Ca,L) inhibition with 50 mmol/L Cd(2+) abolished Ca(2+) spikes, our results demonstrate that during cardiac APs, NCX enhances SR Ca(2+) release by synergistically increasing the efficiency of I (Ca,L)-mediated ECC.
    Archiv für Kreislaufforschung 07/2011; 106(6):967-77. · 7.35 Impact Factor
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    ABSTRACT: Chronic iron overload (CIO) is associated with blood disorders such as thalassemias and hemochromatosis. A major prognostic indicator of survival in patients with CIO is iron-mediated cardiomyopathy characterized by contractile dysfunction and electrical disturbances, including slow heart rate (bradycardia) and heart block. We used a mouse model of CIO to investigate the effects of iron on sinoatrial node (SAN) function. As in humans, CIO reduced heart rate (≈20%) in conscious mice as well as in anesthetized mice with autonomic nervous system blockade and in isolated Langendorff-perfused mouse hearts, suggesting that bradycardia originates from altered intrinsic SAN pacemaker function. Indeed, spontaneous action potential frequencies in SAN myocytes with CIO were reduced in association with decreased L-type Ca(2+) current (I(Ca,L)) densities and positive (rightward) voltage shifts in I(Ca,L) activation. Pacemaker current (I(f)) was not affected by CIO. Because I(Ca,L) in SAN myocytes (as well as in atrial and conducting system myocytes) activates at relatively negative potentials due to the presence of Ca(V)1.3 channels (in addition to Ca(V)1.2 channels), our data suggest that elevated iron preferentially suppresses Ca(V)1.3 channel function. Consistent with this suggestion, CIO reduced Ca(V)1.3 mRNA levels by ≈40% in atrial tissue (containing SAN) and did not lower heart rate in Ca(V)1.3 knockout mice. CIO also induced PR-interval prolongation, heart block, and atrial fibrillation, conditions also seen in Ca(V)1.3 knockout mice. Our results demonstrate that CIO selectively reduces Ca(V)1.3-mediated I(Ca,L), leading to bradycardia, slowing of electrical conduction, and atrial fibrillation as seen in patients with iron overload.
    Circulation Arrhythmia and Electrophysiology 07/2011; 4(5):733-42. · 5.95 Impact Factor
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    ABSTRACT: Rapid electrical conduction in the His–Purkinje system tightly controls spatiotemporal activation of the ventricles. Although recent work has shed much light on the regulation of early specification and morphogenesis of the His–Purkinje system, less is known about how transcriptional regulation establishes impulse conduction properties of the constituent cells. Here we show that Iroquois homeobox gene 3 (Irx3) is critical for efficient conduction in this specialized tissue by antithetically regulating two gap junction–forming connexins (Cxs). Loss of Irx3 resulted in disruption of the rapid coordinated spread of ventricular excitation, reduced levels of Cx40, and ectopic Cx43 expression in the proximal bundle branches. Irx3 directly represses Cx43 transcription and indirectly activates Cx40 transcription. Our results reveal a critical role for Irx3 in the precise regulation of intercellular gap junction coupling and impulse propagation in the heart.
    Proceedings of the National Academy of Sciences 06/2011; · 9.81 Impact Factor
  • Robert A Rose
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    ABSTRACT: In development by Nile Therapeutics Inc, under license from the Mayo Foundation, CD-NP is a chimeric natriuretic peptide in which the 15-amino acid C-terminal tail of Dendroaspis natriuretic peptide is fused to the 22-amino acid human C-type natriuretic peptide. The rationale for its design was to create a peptide with the beneficial cardiovascular and renal effects of native natriuretic peptides, but without a clinically significant hypotensive response. CD-NP is able to bind to all three natriuretic peptide receptors (NPR-A, NPR-B and NPR-C) and, therefore, is unique in being able to increase cyclic guanosine monophosphate production downstream of both NPR-A and NPR-B. Animal studies and human trials demonstrated that CD-NP is safe and improves cardiovascular and renal function without inducing significant levels of hypotension. Preliminary data also suggest improved renal function in human heart failure patients. Ongoing clinical trials are needed to further validate CD-NP as an effective treatment option for heart failure.
    Current opinion in investigational drugs (London, England: 2000) 03/2010; 11(3):349-56. · 3.55 Impact Factor
  • Biophysical Journal 01/2009; 96(3). · 3.67 Impact Factor
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    Robert A Rose, Armand Keating, Peter H Backx
    Circulation Research 11/2008; 103(9):e120. · 11.86 Impact Factor
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    ABSTRACT: Although bone marrow-derived mesenchymal stromal cells (MSCs) may be beneficial in treating heart disease, their ability to transdifferentiate into functional cardiomyocytes remains unclear. Here, bone marrow-derived MSCs from adult female transgenic mice expressing green fluorescent protein (GFP) under the control of the cardiac-specific alpha-myosin heavy chain promoter were cocultured with male rat embryonic cardiomyocytes (rCMs) for 5-15 days. After 5 days in coculture, 6.3% of MSCs became GFP(+) and stained positively for the sarcomeric proteins troponin I and alpha-actinin. The mRNA expression for selected cardiac-specific genes (atrial natriuretic factor, Nkx2.5, and alpha-cardiac actin) in MSCs peaked after 5 days in coculture and declined thereafter. Despite clear evidence for the expression of cardiac genes, GFP(+) MSCs did not generate action potentials or display ionic currents typical of cardiomyocytes, suggesting retention of a stromal cell phenotype. Detailed immunophenotyping of GFP(+) MSCs demonstrated expression of all antigens used to characterize MSCs, as well as the acquisition of additional markers of cardiomyocytes with the phenotype CD45(-)-CD34(+)-CD73(+)-CD105(+)-CD90(+)-CD44(+)-SDF1(+)-CD134L(+)-collagen type IV(+)-vimentin(+)-troponin T(+)-troponin I(+)-alpha-actinin(+)-connexin 43(+). Although cell fusion between rCMs and MSCs was detectable, the very low frequency (0.7%) could not account for the phenotype of the GFP(+) MSCs. In conclusion, we have identified an MSC population displaying plasticity toward the cardiomyocyte lineage while retaining mesenchymal stromal cell properties, including a nonexcitable electrophysiological phenotype. The demonstration of an MSC population coexpressing cardiac and stromal cell markers may explain conflicting results in the literature and indicates the need to better understand the effects of MSCs on myocardial injury. Disclosure of potential conflicts of interest is found at the end of this article.
    Stem Cells 09/2008; 26(11):2884-92. · 7.70 Impact Factor
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    ABSTRACT: Heart rate is controlled by the opposing activities of sympathetic and parasympathetic inputs to pacemaker myocytes in the sinoatrial node (SAN). Parasympathetic activity on nodal myocytes is mediated by acetylcholine-dependent stimulation of M(2) muscarinic receptors and activation of Galpha(i/o) signaling. Although regulators of G protein signaling (RGS) proteins are potent inhibitors of Galpha(i/o) signaling in many tissues, the RGS protein(s) that regulate parasympathetic tone in the SAN are unknown. Our results demonstrate that RGS4 mRNA levels are higher in the SAN compared to right atrium. Conscious freely moving RGS4-null mice showed increased bradycardic responses to parasympathetic agonists compared to wild-type animals. Moreover, anesthetized RGS4-null mice had lower baseline heart rates and greater heart rate increases following atropine administration. Retrograde-perfused hearts from RGS4-null mice showed enhanced negative chronotropic responses to carbachol, whereas SAN myocytes showed greater sensitivity to carbachol-mediated reduction in the action potential firing rate. Finally, RGS4-null SAN cells showed decreased levels of G protein-coupled inward rectifying potassium (GIRK) channel desensitization and altered modulation of acetylcholine-sensitive potassium current (I(KACh)) kinetics following carbachol stimulation. Taken together, our studies establish that RGS4 plays an important role in regulating sinus rhythm by inhibiting parasympathetic signaling and I(KACh) activity.
    Circulation Research 08/2008; 103(5):527-35. · 11.86 Impact Factor

Publication Stats

375 Citations
167.20 Total Impact Points

Institutions

  • 2010–2014
    • Dalhousie University
      Halifax, Nova Scotia, Canada
  • 2003–2012
    • The University of Calgary
      • • Faculty of Medicine
      • • Faculty of Kinesiology
      Calgary, Alberta, Canada
  • 2008–2011
    • University Health Network
      • Department of Cardiology
      Toronto, Ontario, Canada
  • 2006–2011
    • University of Toronto
      • Department of Physiology
      Toronto, Ontario, Canada