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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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Transcription profiling reveals alterations in genes regulating mitochondrial function and oxidative stress response. RNA was isolated from whole ventricular tissues of mice subjected to isoproterenol infusion (CXCR4-KO AAV9.lacZ, CXCR4-KO AAV9.CXCR4, CXCR4-f/f-AAV9.LacZ and CXCR4-f/f-AAV9.CXCR4). mRNA levels of genes that are associated with mitochondrial function (a-c), mitochondrial oxidative stress (d-f), and mitochondrial biogenesis (g-h) were quantified via qRT-PCR performed in triplicate (n=3 mice/group *= p<0.05, **=p<0.01).
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Figure 6: Transcription profiling reveals alterations in genes regulating mitochondrial function and oxidative stress response. RNA was isolated from whole ventricular tissues of mice subjected to isoproterenol infusion (CXCR4-KO AAV9.lacZ, CXCR4-KO AAV9.CXCR4, CXCR4-f/f-AAV9.LacZ and CXCR4-f/f-AAV9.CXCR4). mRNA levels of genes that are associated with mitochondrial function (a-c), mitochondrial oxidative stress (d-f), and mitochondrial biogenesis (g-h) were quantified via qRT-PCR performed in triplicate (n=3 mice/group *= p<0.05, **=p<0.01).

Mentions: Mitochondria are the main intracellular location for fuel generation and it is generally accepted that mitochondrial dysfunction develops in the failing heart.35 The purpose of this section was to outline changes in mitochondrial function, oxidative stress and biogenesis in CXCR4-KO mice and to evaluate whether these changes were attenuated by AAV9.CXCR4 over expression. Indeed, in our model of chronic exposure to isoproterenol-induced hypertrophy, we observed significant changes in mitochondrial gene expression profiles (Figure 6). We first studied genes that are involved in regulating mitochondrial function, e.g. cytochrome c oxidase subunit IV (COX IV), NADH: ubiquinone oxidoreductase complex 1 (Ndufv1 and Ndufa9) ; these genes are important in the electron transport chain.36 Our data demonstrates a significant reduction in mRNA expression of COX4, Ndufv1 and Ndufa9 were detected in CXCR4-KO LacZ-treated mice; while their expression levels were returned to normal with AAV9.CXCR4 gene therapy (Figures 6a, b and c respectively) suggesting a great reduction in mitochondrial function in the absence of cardiac CXCR4.


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)

Transcription profiling reveals alterations in genes regulating mitochondrial function and oxidative stress response. RNA was isolated from whole ventricular tissues of mice subjected to isoproterenol infusion (CXCR4-KO AAV9.lacZ, CXCR4-KO AAV9.CXCR4, CXCR4-f/f-AAV9.LacZ and CXCR4-f/f-AAV9.CXCR4). mRNA levels of genes that are associated with mitochondrial function (a-c), mitochondrial oxidative stress (d-f), and mitochondrial biogenesis (g-h) were quantified via qRT-PCR performed in triplicate (n=3 mice/group *= p<0.05, **=p<0.01).
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Figure 6: Transcription profiling reveals alterations in genes regulating mitochondrial function and oxidative stress response. RNA was isolated from whole ventricular tissues of mice subjected to isoproterenol infusion (CXCR4-KO AAV9.lacZ, CXCR4-KO AAV9.CXCR4, CXCR4-f/f-AAV9.LacZ and CXCR4-f/f-AAV9.CXCR4). mRNA levels of genes that are associated with mitochondrial function (a-c), mitochondrial oxidative stress (d-f), and mitochondrial biogenesis (g-h) were quantified via qRT-PCR performed in triplicate (n=3 mice/group *= p<0.05, **=p<0.01).
Mentions: Mitochondria are the main intracellular location for fuel generation and it is generally accepted that mitochondrial dysfunction develops in the failing heart.35 The purpose of this section was to outline changes in mitochondrial function, oxidative stress and biogenesis in CXCR4-KO mice and to evaluate whether these changes were attenuated by AAV9.CXCR4 over expression. Indeed, in our model of chronic exposure to isoproterenol-induced hypertrophy, we observed significant changes in mitochondrial gene expression profiles (Figure 6). We first studied genes that are involved in regulating mitochondrial function, e.g. cytochrome c oxidase subunit IV (COX IV), NADH: ubiquinone oxidoreductase complex 1 (Ndufv1 and Ndufa9) ; these genes are important in the electron transport chain.36 Our data demonstrates a significant reduction in mRNA expression of COX4, Ndufv1 and Ndufa9 were detected in CXCR4-KO LacZ-treated mice; while their expression levels were returned to normal with AAV9.CXCR4 gene therapy (Figures 6a, b and c respectively) suggesting a great reduction in mitochondrial function in the absence of cardiac CXCR4.

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