The Role of Angiogenic and Wound Repair Factors During CMV-Accelerated Transplant Vascular Sclerosis in Rat Cardiac Transplants

Streblow, Daniel N.; Kreklywich, Craig N.; Andoh, Takeshi F.; Moses, Ashlee V.; Dumortier, Jerome; Smith, Patricia P.; DeFilippis, Victor R.; Früh, Klaus; Nelson, Jay A.; Orloff, Susan L.

doi:10.1111/j.1600-6143.2007.02062.x

Cited by 46 publications

(44 citation statements)

References 26 publications

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“…We have shown that RCMV accelerates the development of TVS/CR in rat heart allografts, although widespread infection is not observed with transplanted organs (39). A comparison of transcriptomes from infected and uninfected heart allografts indicated that RCMV upregulated host genes involved in AG and WH, suggesting that RCMV may accelerate TVS formation through the induction and secretion of AG/WH factors.…”

Section: Resultsmentioning

confidence: 99%

“…AG is an important component of WH, involving inflammation (46), tissue formation, and remodeling, whereby a local milieu created by the coordinated action of growth factors, cytokines, enzymes, extracellular matrix (ECM) components, and inflammatory cells interacts with the injured tissue, the result of which is the reestablishment of a physiological barrier (16). Recent analysis of the RCMV-induced cellular transcriptome demonstrated that a significant number of RCMV-dysregulated genes are involved in WH/AG (39). We hypothesize a mechanism of CMV-accelerated TVS/CR whereby virally induced secretion of cytokines and growth factors is involved.…”

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confidence: 99%

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Human Cytomegalovirus Secretome Contains Factors That Induce Angiogenesis and Wound Healing

Dumortier

Streblow

Moses

et al. 2008

J Virol

102

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Human cytomegalovirus (HCMV) is implicated in the acceleration of a number of vascular diseases including transplant vascular sclerosis (TVS), the lesion associated with chronic rejection (CR) of solid organ transplants. Although the virus persists in the allograft throughout the course of disease, few cells are directly infected by CMV. This observation is in contrast to the global effects that CMV has on the acceleration of TVS/CR, suggesting that CMV infection indirectly promotes the vascular disease process. Recent transcriptome analysis of CMV-infected heart allografts indicates that the virus induces cytokines and growth factors associated with angiogenesis (AG) and wound healing (WH), suggesting that CMV may accelerate TVS/CR through the induction and secretion of AG/WH factors from infected cells. We analyzed virus-free supernatants from HCMV-infected cells (HCMV secretomes) for growth factors, by mass spectrometry and immunoassays, and found that the HCMV secretome contains over 1,000 cellular proteins, many of which are involved in AG/WH. Importantly, functional assays demonstrated that CMV but not herpes simplex virus secretomes not only induce AG/WH but also promote neovessel stabilization and endothelial cell survival for 2 weeks. These findings suggest that CMV acceleration of TVS occurs through virus-induced growth factors and cytokines in the CMV secretome.Numerous epidemiological and animal studies link human cytomegalovirus (HCMV) to the acceleration of vascular diseases including arterial restenosis, atherosclerosis, and transplant vascular sclerosis (TVS) (23,24,37). Recent advances in transplantation have significantly impacted short-term allograft and patient survival; however, long-term graft survival has not improved, due largely to chronic rejection (CR). The prevalence of CR is a concern, since retransplantation is the sole effective therapy. TVS represents the hallmark of CR in vascularized solid organ transplants, and HCMV infection nearly doubles the 5-year rate of cardiac graft failure due to accelerated TVS (11). In heart transplant recipients, ganciclovir, a potent inhibitor of CMV replication, delays the time to allograft rejection (25, 44). A higher incidence of viral DNA in the explant vascular intima from patients with cardiac allograft TVS than in explants without vasculopathy further underscores the influence of HCMV on CR development (47). In kidney transplant patients, the presence of HCMV infection, whether asymptomatic or displaying overt symptoms, negatively impacts allograft survival (9). The role of HCMV in TVS/CR development is clear; however, the mechanisms involved in this process remain illusive for the following reasons: HCMV disease etiology is multifactorial; HCMV is ubiquitous throughout the human population; HCMV infection is lifelong and infects all of the cell types involved in TVS, including smooth muscle cells (SMC), endothelial cells (EC), and macrophages; and HCMV evades the immune system by remaining latent, and clinically silent reactivation is diffic...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Human Cytomegalovirus Secretome Contains Factors That Induce Angiogenesis and Wound Healing

Dumortier

Streblow

Moses

et al. 2008

J Virol

102

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“…9). We performed heart transplants using the F344/Lewis rat model as previously described (25,26,(41)(42)(43) and infected allograft recipients with the r129⌬NT mutant virus (5 ϫ 10 5 PFU), and we compared the time to rejection and the severity of TVS to those of the recipients infected with RCMV-BAC (5 ϫ 10 5 PFU) and uninfected controls. The time to rejection was significantly longer in the RCMV-r129⌬NT recipients (100 Ϯ 0 days, study endpoint) than that inseen in the RCMV-BAC-infected recipients (46.25 Ϯ 2.8 days) (P Ͻ 0.0001) (Fig.…”

Section: Fig 6 Rcmv R129 Induces the Migration Of T Cells Primary Spmentioning

confidence: 99%

“…Total RNA extracted using the TRIzol method (Life Technologies) from infected fibroblasts or tissues from infected rats was analyzed by quantitative reverse transcriptase PCR (RT-PCR) for the presence of r129 gene expression using the primers CG GACCTCAGAACGGACATAC (forward) and TCTCTGCAGGATAGTTG GATCTTG (reverse) and probe AATCTGACCAGACATGTATC. cDNA was generated using Superscript III (Invitrogen Life Technologies), analyzed using an ABI StepOne real-time PCR system, and normalized to L32 (41,42). Gene amplicons served as quantification standards (sensitivity, Յ100 copies/ gene).…”

Section: Cells and Virusesmentioning

confidence: 99%

Cytomegalovirus CC Chemokine Promotes Immune Cell Migration

Vomaske

Denton

Kreklywich

et al. 2012

J Virol

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Cytomegaloviruses manipulate the host chemokine/receptor axis by altering cellular chemokine expression and by encoding multiple chemokines and chemokine receptors. Similar to human cytomegalovirus (HCMV), rat cytomegalovirus (RCMV) encodes multiple CC chemokine-analogous proteins, including r129 (HCMV UL128 homologue) and r131 (HCMV UL130 and MCMV m129/130 homologues). Although these proteins play a role in CMV entry, their function as chemotactic cytokines remains unknown. In the current study, we examined the role of the RCMV chemokine r129 in promoting cellular migration and in accelerating transplant vascular sclerosis (TVS) in our rat heart transplant model. We determined that r129 protein is released into culture supernatants of infected cells and is expressed with late viral gene kinetics during RCMV infection and highly expressed in heart and salivary glands during in vivo rat infections. Using the recombinant r129 protein, we demonstrated that r129 induces migration of lymphocytes isolated from rat peripheral blood, spleen, and bone marrow and from a rat macrophage cell line. Using antibody-mediated cell sorting of rat splenocytes, we demonstrated that r129 induces migration of naïve/central memory CD4؉ T cells. Through ligand-binding assays, we determined that r129 binds rat CC chemokine receptors CCR3, CCR4, CCR5, and CCR7. In addition, mutational analyses identified functional domains of r129 resulting in recombinant proteins that fail to induce migration (r129-⌬NT and -C31A) or alter the chemotactic ability of the chemokine (r129-F43A). Two of the mutant proteins (r129-C31A and -⌬NT) also act as dominant negatives by inhibiting migration induced by wild-type r129. Furthermore, infection of rat heart transplant recipients with RCMV containing the r129-⌬NT mutation prevented CMV-induced acceleration of TVS. Together our findings indicate that RCMV r129 is highly chemotactic, which has important implications during RCMV infection and reactivation and acceleration of TVS.

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“…16,17 Cytomegalovirus is known to be associated with an increased incidence of CAV, which in turn is associated with enhancement of multiple genes associated with wound repair and angiogenesis. 18,19 Costimulatory Signals Costimulatory signals are important for stimulation of T cells and inflammatory cell recruitment into the allograft. 20 It has been reported that CAV correlates with expression of adhesion molecules, including intracellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule-1, and the E-and P-selectins.…”

Section: Pathology Of Cavmentioning

confidence: 99%

Characteristics of Chronic Rejection in Heart Transplantation: Important Elements of Pathogenesis and Future Treatments

Suzuki

Isobe

Morishita

et al. 2010

Circ J

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The Role of Angiogenic and Wound Repair Factors During CMV-Accelerated Transplant Vascular Sclerosis in Rat Cardiac Transplants

Cited by 46 publications

References 26 publications

Human Cytomegalovirus Secretome Contains Factors That Induce Angiogenesis and Wound Healing

Human Cytomegalovirus Secretome Contains Factors That Induce Angiogenesis and Wound Healing

Cytomegalovirus CC Chemokine Promotes Immune Cell Migration

Characteristics of Chronic Rejection in Heart Transplantation: Important Elements of Pathogenesis and Future Treatments

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