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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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CXCR4 knockout mice showed increased perivascular and interstitial fibrosis compared to rescued animals and controls. (a) Ventricular cross sections were taken at the midpapillary level and stained using Masson’s Trichrome. Comparative images shown are composites of images taken at 40x. Panel shown at 200X. (b) Quantification of fibrosis was calculated over the entire section at 40X magnification. The significance of each group is shown as compared to knockouts injected with AAV9.LacZ (*= p<0.05, **= p<0.01). (c) Sirius red stained sections at 200x. Quantification of fibrosis was calculated on sections obtained from CXCR4-KO and control group (CXCR4-f/f) subjected to isoproterenol treatment without any gene therapy.
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Figure 4: CXCR4 knockout mice showed increased perivascular and interstitial fibrosis compared to rescued animals and controls. (a) Ventricular cross sections were taken at the midpapillary level and stained using Masson’s Trichrome. Comparative images shown are composites of images taken at 40x. Panel shown at 200X. (b) Quantification of fibrosis was calculated over the entire section at 40X magnification. The significance of each group is shown as compared to knockouts injected with AAV9.LacZ (*= p<0.05, **= p<0.01). (c) Sirius red stained sections at 200x. Quantification of fibrosis was calculated on sections obtained from CXCR4-KO and control group (CXCR4-f/f) subjected to isoproterenol treatment without any gene therapy.

Mentions: We used conventional Picrosirius Red and Masson's Trichrome staining to assess interstitial fibrosis. Histological staining was done on left ventricular sections at mid-papillary level and images were taken using light microscopy (Figure 4). Cardiac fibrosis was quantified using Masson’s Trichrome staining technique using a composite image of each sample at 40x magnification (Figure 4a). There was a significant increase in fibrosis in CXCR4-KO groups that was not present in the AAV9.CXCR4-rescued group (Figures 4a and c). CXCR4 overexpression prevented ventricular remodeling in the setting of isoproterenol-induced hypertrophy and failure (Figures 4a and b). Our data also confirms that the AAV9.LacZ overexpression does not have any side effects, as similar levels of fibrosis were observed in isoproterenol-stressed CXCR4-KO mice both with and without AAV9.LacZ gene therapy.


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)

CXCR4 knockout mice showed increased perivascular and interstitial fibrosis compared to rescued animals and controls. (a) Ventricular cross sections were taken at the midpapillary level and stained using Masson’s Trichrome. Comparative images shown are composites of images taken at 40x. Panel shown at 200X. (b) Quantification of fibrosis was calculated over the entire section at 40X magnification. The significance of each group is shown as compared to knockouts injected with AAV9.LacZ (*= p<0.05, **= p<0.01). (c) Sirius red stained sections at 200x. Quantification of fibrosis was calculated on sections obtained from CXCR4-KO and control group (CXCR4-f/f) subjected to isoproterenol treatment without any gene therapy.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4016112&req=5

Figure 4: CXCR4 knockout mice showed increased perivascular and interstitial fibrosis compared to rescued animals and controls. (a) Ventricular cross sections were taken at the midpapillary level and stained using Masson’s Trichrome. Comparative images shown are composites of images taken at 40x. Panel shown at 200X. (b) Quantification of fibrosis was calculated over the entire section at 40X magnification. The significance of each group is shown as compared to knockouts injected with AAV9.LacZ (*= p<0.05, **= p<0.01). (c) Sirius red stained sections at 200x. Quantification of fibrosis was calculated on sections obtained from CXCR4-KO and control group (CXCR4-f/f) subjected to isoproterenol treatment without any gene therapy.
Mentions: We used conventional Picrosirius Red and Masson's Trichrome staining to assess interstitial fibrosis. Histological staining was done on left ventricular sections at mid-papillary level and images were taken using light microscopy (Figure 4). Cardiac fibrosis was quantified using Masson’s Trichrome staining technique using a composite image of each sample at 40x magnification (Figure 4a). There was a significant increase in fibrosis in CXCR4-KO groups that was not present in the AAV9.CXCR4-rescued group (Figures 4a and c). CXCR4 overexpression prevented ventricular remodeling in the setting of isoproterenol-induced hypertrophy and failure (Figures 4a and b). Our data also confirms that the AAV9.LacZ overexpression does not have any side effects, as similar levels of fibrosis were observed in isoproterenol-stressed CXCR4-KO mice both with and without AAV9.LacZ gene therapy.

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