Abrogation of CC Chemokine Receptor 9 Ameliorates Ventricular Electrical Remodeling in Mice After Myocardial Infarction

Introduction: Myocardial infarction (MI) triggers structural and electrical remodeling. CC chemokine receptor 9 (CCR9) mediates chemotaxis of inflammatory cells in MI. In our previous study, CCR9 knockout has been found to improve structural remodeling after MI. Here, we further investigate the potential influence of CCR9 on electrical remodeling following MI in order to explore potential new measures to improve the prognosis of MI.Methods and Results: Mice was used and divided into four groups: CCR9+/+/Sham, CCR9−/−/Sham, CCR9+/+/MI, CCR9−/−/MI. Animals were used at 1 week after MI surgery. Cardiomyocytes in the infracted border zone were acutely dissociated and the whole-cell patch clamp was used to record action potential duration (APD), L-type calcium current (ICa,L) and transient outward potassium current (Ito). Calcium transient and sarcoplasmic reticulum (SR) calcium content under stimulation of Caffeine were measured in isolated cardiomyocytes by confocal microscopy. Multielectrode array (MEA) was used to measure the conduction of the left ventricle. The western-blot was performed for the expression level of connexin 43. We observed prolonged APD90, increased ICa,L and decreased Ito following MI, while CCR9 knockout attenuated these changes (APD90: 50.57 ± 6.51 ms in CCR9−/−/MI vs. 76.53 ± 5.98 ms in CCR9+/+/MI, p < 0.05; ICa,L: −13.15 ± 0.86 pA/pF in CCR9−/−/MI group vs. −17.05 ± 1.11 pA/pF in CCR9+/+/MI, p < 0.05; Ito: 4.01 ± 0.17 pA/pF in CCR9−/−/MI group vs. 2.71 ± 0.16 pA/pF in CCR9+/+/MI, p < 0.05). The confocal microscopy results revealed CCR9 knockout reversed the calcium transient and calcium content reduction in sarcoplasmic reticulum following MI. MEA measurements showed improved conduction velocity in CCR9−/−/MI mice (290.1 ± 34.47 cm/s in CCR9−/−/MI group vs. 113.2 ± 14.4 cm/s in CCR9+/+/MI group, p < 0.05). Western-blot results suggested connexin 43 expression was lowered after MI while CCR9 knockout improved its expression.Conclusion: This study shows CCR9 knockout prevents the electrical remodeling by normalizing ion currents, the calcium homeostasis, and the gap junction to maintain APD and the conduction function. It suggests CCR9 is a promising therapeutic target for MI-induced arrhythmia, which warrants further investigation.

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CC chemokine receptor 5 deletion impairs macrophage activation and induces adverse remodeling following myocardial infarction

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01002.2010 ◽

2011 ◽

Vol 300 (4) ◽

pp. H1418-H1426 ◽

Cited By ~ 43

Author(s):

Rogelio Zamilpa ◽

Rushit Kanakia ◽

Joaquin Cigarroa ◽

Qiuxia Dai ◽

G. Patricia Escobar ◽

...

Keyword(s):

Myocardial Infarction ◽

Chemokine Receptor ◽

Macrophage Activation ◽

Activation Markers ◽

Cc Chemokine ◽

Lv Remodeling ◽

Remodeling Index ◽

Adverse Remodeling ◽

Cc Chemokine Receptor 5 ◽

Chemokine Receptor 5

Post-myocardial infarction (MI), chemokine homing of inflammatory cells into the injured left ventricle (LV) regulates ventricular remodeling, in part by stimulating the extracellular matrix response. The CC chemokine receptor 5 (CCR5) is a key chemokine receptor expressed on macrophages, and CCR5 ligands are highly upregulated post-MI. We hypothesized that deletion of CCR5 would attenuate adverse remodeling by decreasing inflammatory cell recruitment. Accordingly, we examined LV function, macrophage recruitment and activation, and collagen content in wild-type (WT, n = 25) and CCR5 null ( n = 33) mice at 7 days post-MI. Both groups had similar infarct sizes (44 ± 2% in WT and 42 ± 2% in CCR5 null; P = 0.37). However, the LV remodeling index (end diastolic volume/LV mass) increased to a larger extent in CCR5 null (1.28 ± 0.08 μl/mg for CCR5 null and 1.02 ± 0.06 μl/mg for WT; P < 0.05). Although numbers of infiltrated macrophages were similar in WT and CCR5 null mice, CCR5-deficient macrophages isolated from the infarct zone displayed >50% decrease in gene expression levels of proinflammatory activation markers (interleukin-1β, interleukin-6, and tumor necrosis factor-α), as well as anti-inflammatory activation markers (arginase 1, CD163, mannose receptor, and transforming growth factor-β1) compared with WT (all P < 0.05). Concomitant with the reduced macrophage activation, heat shock protein-47 and collagen type I precursor levels in the infarct region decreased in the CCR5 null (1.2 ± 0.3 units in the CCR5 null and 2.3 ± 0.4 units in the WT; P < 0.05), while collagen fragments increased (88.3 ± 5.9 units in the CCR5 null and 32.7 ± 8.5 units in the WT; P < 0.05). We conclude that CCR5 deletion impairs LV remodeling by hindering macrophage activation, which stimulates an imbalance in collagen metabolism and increases the remodeling index.

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Initial Contractile Response of Isolated Rat Heart Cells to Halothane, Enflurane, and Isoflurane

Anesthesiology ◽

10.1097/00000542-199701000-00018 ◽

1997 ◽

Vol 86 (1) ◽

pp. 137-146 ◽

Cited By ~ 12

Author(s):

David M. Wheeler ◽

Todd R. Rice ◽

William H. duBell ◽

Harold A. Spurgeon

Keyword(s):

Sarcoplasmic Reticulum ◽

Intracellular Calcium ◽

Calcium Content ◽

Calcium Transient ◽

Temporary Increase ◽

Heart Cells ◽

Patch Clamp Technique ◽

Intracellular Calcium Transient ◽

Sarcoplasmic Reticulum Calcium ◽

In Cells

Background In several beating cardiac muscle preparations, a short-lived increase in twitch tension or amplitude has been observed when they were exposed abruptly to solutions containing halothane or enflurane. As exposure to the anesthetics was continued, the expected negative inotropic effect became evident after the short-lived increase in twitch. No such increase in twitch has been reported during exposure to isoflurane. It has been hypothesized that this short-lived increase in twitch is caused by an enhancement of calcium release from the sarcoplasmic reticulum, but other mechanisms have not been excluded. Methods Freshly isolated, single rat ventricular cells were stimulated to beat at room temperature and abruptly exposed to solutions containing halothane (0.25-0.64 mM), enflurane (0.69-1 mM), or isoflurane (0.31-0.54 mM). During these exposures, twitch amplitude was measured and intracellular calcium concentration was followed using the calcium-sensitive dye indo-1. In some experiments, the whole-cell patch-clamp technique was used to measure membrane current. In addition, in several cells the sarcoplasmic reticulum calcium content was assessed through the response to brief pulses of caffeine. Results Both the twitch amplitude and the intracellular calcium transient were increased temporarily in cells abruptly exposed to halothane or enflurane. No such behavior was found with isoflurane. After continued exposure to all three agents, both the twitch amplitude and the calcium transient were less than control. During the beats exhibiting an increase in twitch, no alteration in the relation between cell length (twitch amplitude) and the intracellular calcium transient was found compared with control conditions. In addition, the temporary increase in twitch amplitude occurred in cells contracting under voltage-clamp control when halothane was introduced, and it was not associated with any increase in the calcium current. The sarcoplasmic reticulum calcium content at the time of the halothane-induced increase in twitch also was not increased. Conclusions The short-lived increase in twitch after abrupt exposure to halothane or enflurane is related to increased intracellular calcium during the beat and not to any changes in myofilament sensitivity to calcium. Because these results eliminate most alternative explanations for this phenomenon, the authors conclude that halothane, and probably also enflurane, increases the fraction of calcium released from the sarcoplasmic reticulum with each heart beat. Isoflurane appears to lack this action.

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Polymorphisms in the CC-chemokine receptor-2 (CCR2) and -5 (CCR5) genes and risk of myocardial infarction among Tunisian male patients

Clinical Biochemistry ◽

10.1016/j.clinbiochem.2012.01.004 ◽

2012 ◽

Vol 45 (6) ◽

pp. 420-424 ◽

Cited By ~ 1

Author(s):

Amani Kallel ◽

Salem Abdessalem ◽

Yosra Sédiri ◽

Mohamed Sami Mourali ◽

Moncef Feki ◽

...

Keyword(s):

Myocardial Infarction ◽

Chemokine Receptor ◽

Cc Chemokine ◽

Cc Chemokine Receptor 2 ◽

Male Patients

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CC chemokine receptor 5 (CCR5) deletion polymorphism does not protect Czech males against early myocardial infarction

Journal of Internal Medicine ◽

10.1111/j.1365-2796.2005.01491.x ◽

2005 ◽

Vol 257 (6) ◽

pp. 564-566 ◽

Cited By ~ 17

Author(s):

J. Petrkova ◽

Z. Cermakova ◽

J. Lukl ◽

M. Petrek

Keyword(s):

Myocardial Infarction ◽

Chemokine Receptor ◽

Deletion Polymorphism ◽

Cc Chemokine ◽

Cc Chemokine Receptor 5 ◽

Chemokine Receptor 5

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Role of polymorphisms of CC-chemokine receptor-5 gene in acute myocardial infarction and biological implications for longevity

Haematologica ◽

10.3324/haematol.12239 ◽

2008 ◽

Vol 93 (4) ◽

pp. 637-638 ◽

Cited By ~ 20

Author(s):

C. R. Balistreri ◽

G. Candore ◽

M. Caruso ◽

E. Incalcaterra ◽

C. Franceschi ◽

...

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Chemokine Receptor ◽

Cc Chemokine ◽

Cc Chemokine Receptor 5 ◽

Chemokine Receptor 5

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CC Chemokine Receptor 5 Directs Macrophage Function Following Myocardial Infarction

The FASEB Journal ◽

10.1096/fasebj.24.1_supplement.1029.10 ◽

2010 ◽

Vol 24 (S1) ◽

Author(s):

Rogelio Zamilpa ◽

Rushit Kanakia ◽

Joaquin Cigarroa ◽

Hernan Martinez ◽

Fabio Jimenez ◽

...

Keyword(s):

Myocardial Infarction ◽

Chemokine Receptor ◽

Macrophage Function ◽

Cc Chemokine ◽

Cc Chemokine Receptor 5 ◽

Chemokine Receptor 5

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CC chemokine receptor (CCR)2 polymorphism in Czech patients with myocardial infarction

Immunology Letters ◽

10.1016/s0165-2478(03)00053-1 ◽

2003 ◽

Vol 88 (1) ◽

pp. 53-55 ◽

Cited By ~ 34

Author(s):

Jana Petrkova ◽

Zuzana Cermakova ◽

Jiri Drabek ◽

Jan Lukl ◽

Martin Petrek

Keyword(s):

Myocardial Infarction ◽

Chemokine Receptor ◽

Cc Chemokine

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Abstract 15486: Intramyocardial Gene Therapy With a Novel Angiogenic Molecule, Pellino-1 Preserves Functions and Increases Cell Survivability in a Mouse Myocardial Infarction Model

Circulation ◽

10.1161/circ.130.suppl_2.15486 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Vladimir Coca-Soliz ◽

Leonidas Tapias ◽

Vaithinathan Selvaraju ◽

Mahesh Thirunavukkarasu ◽

J.Alexander Palesty ◽

...

Keyword(s):

Myocardial Infarction ◽

Gene Therapy ◽

Western Blot ◽

Gap Junction ◽

Blot Analysis ◽

Western Blot Analysis ◽

Connexin 43 ◽

Border Zone ◽

Junction Protein ◽

Gap Junction Protein

Introduction: Our present study attempted to evaluate the effect of Pellino1 (Peli1) overexpression on angiogenesis and myocardial function by intramyocardial administration of adenovirus encoding Peli1 (Ad.Peli1) following myocardial infarction (MI) in mice. Methods: CD-1/ICR mice were divided into six groups: Control Sham (CS); Control MI (CMI); Adeno-LacZ Sham (Ad.LacZS); Adeno-LacZ MI (Ad.LacZMI); Adeno-Pellino1 Sham (Ad.Peli1S) and Adeno-Pellino1 MI (Ad.Peli1MI). MI was induced by permanent ligation of left anterior descending coronary artery (LAD). Following LAD ligation or sham surgery Ad.LacZ or Ad.Peli1 was injected at 4 border zone sites to either Ad.LacZS/Ad.LaczMI or Ad.Peli1S/Ad.Peli1MI groups respectively. Heart tissue was collected 24 hours post MI for Western blot analysis,4 days for gap junction protein and 30 days later for immunohistochemistry after echocardiographic analysis. Results: Echocardiographic analysis revealed increased ejection fraction [48±0.75 vs. 33±0.98% (n=10-11);p<0.05] and fractional shortening [24±0.49 vs. 16±0.51% (n=10-11) p<0.05] along with decreased LVIDs [3.74±0.14 vs. 5.21±0.19(mm) (n=10-11); p<0.05] in the Ad.Peli1MI as compared to the Ad.LacZMI group. Immunohistochemical analysis for fibrosis with picrosirius red staining exhibited a decrease in collagen deposition in Ad.Peli1MI group [16±1.05 vs. 29±2.05% (n=8); p<0.0001] as compared to Ad.LacZMI group. Connexin-43, a major ventricular gap junction protein was found to be significantly expressed in Ad.Peli1MI group compared to Ad.LacZMI. Ad.Peli1 gene therapy after MI increased capillary density [2342±122 vs. 1776±54 counts/mm2 (n=6);p<0.05] as compared to the Ad.LacZMI group. Western blot analysis 24h after MI revealed increased phosphorylation of Akt (3.4 fold), eNOS (1.9fold) and MK2 (1.7fold) with Ad.Peli1 treatment compared to Ad.LacZ. Similar experiments conducted with Peli1KO mice also revealed decreased DNA binding activity of NFκB activity by Gel-shift analysis 8 h after MI. Conclusion: Taken together, these data shows the potential of Peli1 gene therapy in inducing angiogenesis and reducing ventricular remodeling in the infarcted myocardium.

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