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Deletion of CXCR4 in cardiomyocytes exacerbates cardiac dysfunction following isoproterenol administration.

Wang ER, Jarrah AA, Benard L, Chen J, Schwarzkopf M, Hadri L, Tarzami ST - Gene Ther. (2014)

Bottom Line: CXCR4 ablation increased susceptibility to isoproterenol-induced heart failure, by upregulating apoptotic markers and reducing mitochondrial function; cardiac function decreases whereas fibrosis increases.In addition, CXCR4 expression was rescued with the use of cardiotropic adeno-associated viral-9 vectors.Our results represent the first evidence that SDF-1/CXCR4 signaling mediates acute cardioprotection through modulating beta-adrenergic receptor signaling in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Cardiovascular Research Center, Mount Sinai School of Medicine, New York, NY, USA.

ABSTRACT
Altered alpha- and beta-adrenergic receptor signaling is associated with cardiac hypertrophy and failure. Stromal cell-derived factor-1α (SDF-1α) and its cognate receptor CXCR4 have been reported to mediate cardioprotection after injury through the mobilization of stem cells into injured tissue. However, little is known regarding whether SDF-1/CXCR4 induces acute protection following pathological hypertrophy and if so, by what molecular mechanism. We have previously reported that CXCR4 physically interacts with the beta-2 adrenergic receptor and modulates its downstream signaling. Here we have shown that CXCR4 expression prevents beta-adrenergic receptor-induced hypertrophy. Cardiac beta-adrenergic receptors were stimulated with the implantation of a subcutaneous osmotic pump administrating isoproterenol and CXCR4 expression was selectively abrogated in cardiomyocytes using Cre-loxP-mediated gene recombination. CXCR4 knockout mice showed worsened fractional shortening and ejection fraction. CXCR4 ablation increased susceptibility to isoproterenol-induced heart failure, by upregulating apoptotic markers and reducing mitochondrial function; cardiac function decreases whereas fibrosis increases. In addition, CXCR4 expression was rescued with the use of cardiotropic adeno-associated viral-9 vectors. CXCR4 gene transfer reduced cardiac apoptotic signaling, improved mitochondrial function and resulted in a recovered cardiac function. Our results represent the first evidence that SDF-1/CXCR4 signaling mediates acute cardioprotection through modulating beta-adrenergic receptor signaling in vivo.

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AAV9.CXCR4 or AAV9.LacZ control was delivered to the heart via tail vein injection one month prior to pump insertion. (a) Echocardiography was performed at baseline, one week and two weeks post isoproterenol-treatment and showed significant dilation and loss of function that was prevented in gene therapy rescued animals. (b) In vivo hemodynamic data were acquired using a pressure-volume conductance catheter via an open-chest approach. Pre-load reduction studies were done by transiently occluding the inferior vena cava. CXCR4-KO-AAV9.LacZ (red) CXCR4-KO-AAV9.CXCR4 (green) CXCR4-f/f-AAV9.LacZ (blue) and CXCR4-f/f-AAV9.CXCR4 (orange) are shown at baseline and 3 weeks post isoproterenol treatment. AAV9.CXCR4 and AAV9.LacZ had no effects on cardiac function in the absence of isoproterenol treatment as demonstrated in the inset by unchanged ejection fraction prior to isoproterenol infusion. (c) Heart function (ejection fraction and fractional shortening) was significantly reduced in CXCR4-KO AAV9.LacZ group as compared to other groups. (d) Heart weight/body weight ratio. CXCR4-KO exhibited greater heart weight–body weight (HW:BW) ratio after isoproterenol treatment (n=5 mice/group).
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Figure 2: AAV9.CXCR4 or AAV9.LacZ control was delivered to the heart via tail vein injection one month prior to pump insertion. (a) Echocardiography was performed at baseline, one week and two weeks post isoproterenol-treatment and showed significant dilation and loss of function that was prevented in gene therapy rescued animals. (b) In vivo hemodynamic data were acquired using a pressure-volume conductance catheter via an open-chest approach. Pre-load reduction studies were done by transiently occluding the inferior vena cava. CXCR4-KO-AAV9.LacZ (red) CXCR4-KO-AAV9.CXCR4 (green) CXCR4-f/f-AAV9.LacZ (blue) and CXCR4-f/f-AAV9.CXCR4 (orange) are shown at baseline and 3 weeks post isoproterenol treatment. AAV9.CXCR4 and AAV9.LacZ had no effects on cardiac function in the absence of isoproterenol treatment as demonstrated in the inset by unchanged ejection fraction prior to isoproterenol infusion. (c) Heart function (ejection fraction and fractional shortening) was significantly reduced in CXCR4-KO AAV9.LacZ group as compared to other groups. (d) Heart weight/body weight ratio. CXCR4-KO exhibited greater heart weight–body weight (HW:BW) ratio after isoproterenol treatment (n=5 mice/group).

Mentions: Ejection fraction (EF), fractional shortening (FS), end-systolic and end-diastolic left ventricular internal dimensions (LVIDs and LVIDd), interventricular septum thickness (IVSs and IVSd), and left ventricular posterior wall thickness (LVPWs and LVPWd) were assessed (Table 1, Supplementary Table S1). Representative images of short axis m-mode are shown (Figure 2a). At three weeks post pump insertion, in vivo hemodynamics were collected and heart weight–body weight (HW:BW) ratio was calculated (Table 2, Figures 2b-d,). Representative sets of pressure-volume loops from all treated groups were selected (Figure 2b). Our data demonstrates that CXCR4-KO mice exhibited depressed cardiac function as indicated by a reduction in EF and FS (Figure 2c), as well as increased end-systolic and end-diastolic volumes (Table 1 and 2) and greater HW:BW ratio following isoproterenol treatment (Figure 2d). CXCR4-KO mice that had been injected with AAV9.CXCR4 were rescued from cardiac dysfunction and performance was restored to control group (CXCR4-f/f) levels (Figure 2c). Specifically, CXCR4-treated mice showed reduced end-systolic and end-diastolic volumes (Figures 2a, c), and had reduced HW:BW’s compared to LacZ controls (Figure 2d). Loss of EF and FS was also prevented in knockout mice overexpressing CXCR4 (P < 0.05) (Table 2, Figure 2c).


Deletion of CXCR4 in cardiomyocytes exacerbates cardiac dysfunction following isoproterenol administration.

Wang ER, Jarrah AA, Benard L, Chen J, Schwarzkopf M, Hadri L, Tarzami ST - Gene Ther. (2014)

AAV9.CXCR4 or AAV9.LacZ control was delivered to the heart via tail vein injection one month prior to pump insertion. (a) Echocardiography was performed at baseline, one week and two weeks post isoproterenol-treatment and showed significant dilation and loss of function that was prevented in gene therapy rescued animals. (b) In vivo hemodynamic data were acquired using a pressure-volume conductance catheter via an open-chest approach. Pre-load reduction studies were done by transiently occluding the inferior vena cava. CXCR4-KO-AAV9.LacZ (red) CXCR4-KO-AAV9.CXCR4 (green) CXCR4-f/f-AAV9.LacZ (blue) and CXCR4-f/f-AAV9.CXCR4 (orange) are shown at baseline and 3 weeks post isoproterenol treatment. AAV9.CXCR4 and AAV9.LacZ had no effects on cardiac function in the absence of isoproterenol treatment as demonstrated in the inset by unchanged ejection fraction prior to isoproterenol infusion. (c) Heart function (ejection fraction and fractional shortening) was significantly reduced in CXCR4-KO AAV9.LacZ group as compared to other groups. (d) Heart weight/body weight ratio. CXCR4-KO exhibited greater heart weight–body weight (HW:BW) ratio after isoproterenol treatment (n=5 mice/group).
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Figure 2: AAV9.CXCR4 or AAV9.LacZ control was delivered to the heart via tail vein injection one month prior to pump insertion. (a) Echocardiography was performed at baseline, one week and two weeks post isoproterenol-treatment and showed significant dilation and loss of function that was prevented in gene therapy rescued animals. (b) In vivo hemodynamic data were acquired using a pressure-volume conductance catheter via an open-chest approach. Pre-load reduction studies were done by transiently occluding the inferior vena cava. CXCR4-KO-AAV9.LacZ (red) CXCR4-KO-AAV9.CXCR4 (green) CXCR4-f/f-AAV9.LacZ (blue) and CXCR4-f/f-AAV9.CXCR4 (orange) are shown at baseline and 3 weeks post isoproterenol treatment. AAV9.CXCR4 and AAV9.LacZ had no effects on cardiac function in the absence of isoproterenol treatment as demonstrated in the inset by unchanged ejection fraction prior to isoproterenol infusion. (c) Heart function (ejection fraction and fractional shortening) was significantly reduced in CXCR4-KO AAV9.LacZ group as compared to other groups. (d) Heart weight/body weight ratio. CXCR4-KO exhibited greater heart weight–body weight (HW:BW) ratio after isoproterenol treatment (n=5 mice/group).
Mentions: Ejection fraction (EF), fractional shortening (FS), end-systolic and end-diastolic left ventricular internal dimensions (LVIDs and LVIDd), interventricular septum thickness (IVSs and IVSd), and left ventricular posterior wall thickness (LVPWs and LVPWd) were assessed (Table 1, Supplementary Table S1). Representative images of short axis m-mode are shown (Figure 2a). At three weeks post pump insertion, in vivo hemodynamics were collected and heart weight–body weight (HW:BW) ratio was calculated (Table 2, Figures 2b-d,). Representative sets of pressure-volume loops from all treated groups were selected (Figure 2b). Our data demonstrates that CXCR4-KO mice exhibited depressed cardiac function as indicated by a reduction in EF and FS (Figure 2c), as well as increased end-systolic and end-diastolic volumes (Table 1 and 2) and greater HW:BW ratio following isoproterenol treatment (Figure 2d). CXCR4-KO mice that had been injected with AAV9.CXCR4 were rescued from cardiac dysfunction and performance was restored to control group (CXCR4-f/f) levels (Figure 2c). Specifically, CXCR4-treated mice showed reduced end-systolic and end-diastolic volumes (Figures 2a, c), and had reduced HW:BW’s compared to LacZ controls (Figure 2d). Loss of EF and FS was also prevented in knockout mice overexpressing CXCR4 (P < 0.05) (Table 2, Figure 2c).

Bottom Line: CXCR4 ablation increased susceptibility to isoproterenol-induced heart failure, by upregulating apoptotic markers and reducing mitochondrial function; cardiac function decreases whereas fibrosis increases.In addition, CXCR4 expression was rescued with the use of cardiotropic adeno-associated viral-9 vectors.Our results represent the first evidence that SDF-1/CXCR4 signaling mediates acute cardioprotection through modulating beta-adrenergic receptor signaling in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Cardiovascular Research Center, Mount Sinai School of Medicine, New York, NY, USA.

ABSTRACT
Altered alpha- and beta-adrenergic receptor signaling is associated with cardiac hypertrophy and failure. Stromal cell-derived factor-1α (SDF-1α) and its cognate receptor CXCR4 have been reported to mediate cardioprotection after injury through the mobilization of stem cells into injured tissue. However, little is known regarding whether SDF-1/CXCR4 induces acute protection following pathological hypertrophy and if so, by what molecular mechanism. We have previously reported that CXCR4 physically interacts with the beta-2 adrenergic receptor and modulates its downstream signaling. Here we have shown that CXCR4 expression prevents beta-adrenergic receptor-induced hypertrophy. Cardiac beta-adrenergic receptors were stimulated with the implantation of a subcutaneous osmotic pump administrating isoproterenol and CXCR4 expression was selectively abrogated in cardiomyocytes using Cre-loxP-mediated gene recombination. CXCR4 knockout mice showed worsened fractional shortening and ejection fraction. CXCR4 ablation increased susceptibility to isoproterenol-induced heart failure, by upregulating apoptotic markers and reducing mitochondrial function; cardiac function decreases whereas fibrosis increases. In addition, CXCR4 expression was rescued with the use of cardiotropic adeno-associated viral-9 vectors. CXCR4 gene transfer reduced cardiac apoptotic signaling, improved mitochondrial function and resulted in a recovered cardiac function. Our results represent the first evidence that SDF-1/CXCR4 signaling mediates acute cardioprotection through modulating beta-adrenergic receptor signaling in vivo.

Show MeSH
Related in: MedlinePlus