Bone Marrow-Derived Cells Contribute to Fibrosis in the Chronically Failing Heart

Chu, Po‐Yin; Mariani, Justin A.; Finch, Samara; McMullen, Julie R.; Sadoshima, Junichi; Marshall, Tanneale; Kaye, David M.

doi:10.2353/ajpath.2010.090574

Cited by 88 publications

(83 citation statements)

References 34 publications

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“…Previously we showed that SDF-1 stimulates both the homing and proliferation of cardiac fibroblasts, 14 and in this study we demonstrated the induction of myocardial SDF-1 expression in response to mineralocorticoid excess. This raises the possibility that SDF-1 could be directly responsible for the development of fibrosis, through stimulation of fibroblasts and/or recruitment of fibrocytes.…”

Section: Chu Et Al Sdf-1/cxcr4 Pathway In Mineralocorticoid Excessmentioning

confidence: 72%

“…Consistent with this concept, we recently demonstrated that recruitment of bone marrow-derived fibrocytes contributes significantly to cardiac fibrosis in an experimental model of heart failure. 14 In conjunction, we showed that this process was associated with an increase in local levels of stromal-derived factor 1 (SDF-1), which could be driven by angiotensin II. SDF-1 is a chemotactic protein that is known to play a critical role in the trafficking of various bone marrow derived cells including lymphocytes, fibrocytoid cells, and hematopoietic stem cells [15][16][17] through interaction with its cognate receptor, CXCR4.…”

Section: Clinical Perspective On P 658mentioning

confidence: 85%

“…This hypothesis was based on recent data from our group showing that SDF-1 expression is increased in heart failure and that in cell culture models angiotensin II increases SDF-1 secretion. 14 In further support of the putative role of SDF-1 in the setting of mineralocorticoid excess, it has also been shown that aldosterone increases SDF-1 mRNA levels. 27 In keeping with this hypothesis, we showed that the selective CXCR4 antagonist AMD3465 markedly attenuated the development of hypertension and T-lymphocyte accumulation in the kidney and heart.…”

Section: Discussionmentioning

confidence: 99%

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CXCR4 Antagonism Attenuates the Cardiorenal Consequences of Mineralocorticoid Excess

Chu

Zatta

Kiriazis

et al. 2011

Circ: Heart Failure

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Background-Extensive evidence implicates aldosterone excess in the development and progression of cardiovascular disease states including hypertension, metabolic syndrome, cardiac hypertrophy, heart failure, and cardiorenal fibrosis. Recent studies show that activation of inflammatory cascade may play a specific role in the sequelae of mineralocorticoid activation, although the linking mechanism remains unclear. We tested the possibility that secondary stimulation of the stromal-derived factor 1/CXC chemokine receptor 4 (SDF-1/CXCR4) pathway plays a contributory role. Methods and Results-We investigated the effect of the highly selective CXCR4 antagonist AMD3465 (6 mg/kg per day for 6 weeks through minipump) in dexoycorticosterone acetate (DOCA)-treated, uninephrectomized mice. CXCR4 antagonism significantly attenuated the induction of cardiac fibrosis, renal fibrosis, hypertension, and left ventricular hypertrophy by DOCA. Mineralocorticoid excess also stimulated the accumulation of T-lymphocytes in the heart and kidney and this was significantly blunted by CXCR4 inhibition. Conclusions-Taken together, these data strongly implicate the SDF-1/CXCR4 axis in the pathogenesis of mineralocorticoid excess induced hypertension, inflammation, and cardiorenal fibrosis. This insight provides a new potential therapeutic approach for the treatment of specific aspects of mineralocorticoid mediated cardiovascular disease. (Circ Heart Fail. 2011;4:651-658.)

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Section: Chu Et Al Sdf-1/cxcr4 Pathway In Mineralocorticoid Excessmentioning

confidence: 72%

Section: Clinical Perspective On P 658mentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

CXCR4 Antagonism Attenuates the Cardiorenal Consequences of Mineralocorticoid Excess

Chu

Zatta

Kiriazis

et al. 2011

Circ: Heart Failure

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“…20,21 There was a significant increase in CXCL12 mRNA (3.2±0.4 fold; P¼0.008) expression in the myocardium of animals exposed to AngII at 7 days compared with the baseline expression of the normalized housekeeping gene ( Figure 6). Similarly, there was a significant increase in CCL2 mRNA expression in the myocardium of AngII-exposed animals (3.8±1.0 fold; P¼0.015).…”

Section: Myocardial Profibrotic Cytokine Environmentmentioning

confidence: 99%

Myocardial migration by fibroblast progenitor cells is blood pressure dependent in a model of angII myocardial fibrosis

et al. 2012

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Activation of the renin-angiotensin system (RAS) is thought to promote myocardial fibrosis. However, it is unclear whether this physiological fibrotic response results from chronic hemodynamic stress or from direct cellular signaling. Male C57B/6 mice were randomly assigned to receive angiotensin II (AngII) (2.0 lg kg À1 min À1 ), AngII+hydralazine (6.9 lg kg À1 min À1 ) or saline (control) via osmotic pumps for 7 days. Blood pressure was measured via noninvasive plethysmography. Hearts were harvested and processed for analysis. Cellular infiltration and collagen deposition were analyzed using histological staining. Molecular mediators were assessed using quantitative RT-PCR. As previously described, animals that received AngII developed hypertension and multifocal cellular infiltration by SMA + /CD133 + fibroblast progenitors followed by collagen deposition. The coadministration of hydralazine with AngII completely inhibited the hypertensive effects of AngII (Pp0.01) and resulted in minimal cellular infiltration and minimal collagen deposition. These findings were in the context of persistent RAS activation, which was evidenced by elevation in serum aldosterone levels in animals that received AngII or AngII+hydralazine compared with animals that received saline. At the molecular level, infusion of AngII resulted in the significant upregulation of profibrotic factors (connective tissue growth factor-7.8±0.7 fold), proinflammatory mediators (TNFa-4.6±0.8 fold; IL-1b-6.4±2.6 fold) and chemokines (CCL2-3.8 ± 1.0 fold; CXCL12-3.2 ± 0.4 fold), which were inhibited when hydralazine was also infused. We provide evidence that myocardial infiltration by fibroblast progenitor cells secondary to AngII and the resultant fibrosis can be prevented by the addition of hydralazine. Furthermore, the beneficial effects of hydralazine were observed while maintaining RAS activation, suggesting that the mechanism of fibrosis is blood pressure dependent.

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“…However, a potential developmental contribution of hematopoietic progenitors or lineages to cardiac fibroblasts cannot be excluded; such a phenomenon could reconcile the transplantation data with previous studies. 17 To examine whether cardiac fibroblasts have an embryonic hematopoietic origin, we generated Vav Cre/+ ;R26R mT/mG mice, in which GFP labels hematopoietic progenitors and their progeny (Online Figure IIIF). 18 We did not observe any GFP expression in the Thy1 + HE − cell compartment (Online Figure IIIG).…”

Section: Bm and Circulating Cells Do Not Generate Cardiac Fibroblastsmentioning

confidence: 99%

Developmental Heterogeneity of Cardiac Fibroblasts Does Not Predict Pathological Proliferation and Activation

Ali

Ranjbarvaziri²,

Talkhabi³

et al. 2014

Circ Res

260

296

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Rationale: Fibrosis is mediated partly by extracellular matrix–depositing fibroblasts in the heart. Although these mesenchymal cells are reported to have multiple embryonic origins, the functional consequence of this heterogeneity is unknown. Objective: We sought to validate a panel of surface markers to prospectively identify cardiac fibroblasts. We elucidated the developmental origins of cardiac fibroblasts and characterized their corresponding phenotypes. We also determined proliferation rates of each developmental subset of fibroblasts after pressure overload injury. Methods and Results: We showed that Thy1 + CD45 − CD31 − CD11b − Ter119 − cells constitute the majority of cardiac fibroblasts. We characterized these cells using flow cytometry, epifluorescence and confocal microscopy, and transcriptional profiling (using reverse transcription polymerase chain reaction and RNA-seq). We used lineage tracing, transplantation studies, and parabiosis to show that most adult cardiac fibroblasts derive from the epicardium, a minority arises from endothelial cells, and a small fraction from Pax3-expressing cells. We did not detect generation of cardiac fibroblasts by bone marrow or circulating cells. Interestingly, proliferation rates of fibroblast subsets on injury were identical, and the relative abundance of each lineage remained the same after injury. The anatomic distribution of fibroblast lineages also remained unchanged after pressure overload. Furthermore, RNA-seq analysis demonstrated that Tie2-derived and Tbx18-derived fibroblasts within each operation group exhibit similar gene expression profiles. Conclusions: The cellular expansion of cardiac fibroblasts after transaortic constriction surgery was not restricted to any single developmental subset. The parallel proliferation and activation of a heterogeneous population of fibroblasts on pressure overload could suggest that common signaling mechanisms stimulate their pathological response.

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Bone Marrow-Derived Cells Contribute to Fibrosis in the Chronically Failing Heart

Cited by 88 publications

References 34 publications

CXCR4 Antagonism Attenuates the Cardiorenal Consequences of Mineralocorticoid Excess

CXCR4 Antagonism Attenuates the Cardiorenal Consequences of Mineralocorticoid Excess

Myocardial migration by fibroblast progenitor cells is blood pressure dependent in a model of angII myocardial fibrosis

Developmental Heterogeneity of Cardiac Fibroblasts Does Not Predict Pathological Proliferation and Activation

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