Prevention of Cardiac Allograft Arteriosclerosis by Protein Tyrosine Kinase Inhibitor Selective for Platelet-Derived Growth Factor Receptor

Sihvola, Roope; Koskinen, Petri; Myllärniemi, Marjukka; Loubtchenkov, Michael; Häyry, P; Buchdunger, Elisabeth; Lemström, Karl

doi:10.1161/01.cir.99.17.2295

Cited by 58 publications

(36 citation statements)

References 23 publications

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“…Finally, in addition to inducing direct vascular endothelial injury, macrophages may promote an aberrant healing response fostering allograft arteriopathy through the production of a large array of growth factors (such as PDGF, IGF-1 and TGF-b). Many of these growth factors are known to promote vascular smooth muscle proliferation and migration, essential steps in the evolution of the neointimal proliferation that characterizes CAV (2,(5)(6)(7).…”

Section: Discussionmentioning

confidence: 99%

“…They can produce both reactive oxygen species and potent degradative enzymes which might cause adventitious injury of allograft vascular endothelium (4). Finally, macrophages can produce growth factors such as transforming growth factorbeta (TGF-b), platelet-derived growth factor (PDGF) and insulin-like growth factor-1 (IGF-1) and chemokines such as MIG/CXCL9 and RANTES/CCL5, all of which might drive the proliferation of neointimal cells (2,(5)(6)(7)(8)(9). In this study, we evaluate the contribution of macrophages to chronic lesion formation by depleting macrophages from recipients of parental to F 1 cardiac transplants, a system that reliably produces CAV lesions, independent of T-cell or antibody alloreactivity (10).…”

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confidence: 99%

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Macrophage Depletion Suppresses Cardiac Allograft Vasculopathy in Mice

Kitchens

Chase

Uehara

et al. 2007

American Journal of Transplantation

106

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Macrophage Depletion Suppresses Cardiac Allograft Vasculopathy in Mice

Kitchens

Chase

Uehara

et al. 2007

American Journal of Transplantation

106

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“…Specifically, in different animal models of acute arterial injury by balloon catheterization, neointimal SMC accumulation was reduced by the administration of various PDGF pathway inhibitors, including neutralizing PDGF (AB) antibodies (Ferns et al 1991;Lewis et al 2001), PDGF-B aptamers (Leppänen et al 2000), PDGFR kinase inhibitors (Banai et al 1998;Yamasaki et al 2001), and PDGFR-neutralizing antibodies (Giese et al 1999;Hart et al 1999). Restenosis following angioplasty of atherosclerotic vessels in minipigs (Bilder et al 1999) and chronic cardiac transplant rejection-induced atherosclerosis in rats (Sihvola et al 1999) were also inhibited by PDGFR-blocking kinase inhibitors. In ApoE-deficient mice, atherosclerotic lesions were inhibited by neutralizing PDGFR-␤ antibodies (Sano et al 2001) and a PDGFR blocking kinase inhibitor (Kozaki et al 2002).…”

Section: Atherosclerosis and Restenosismentioning

confidence: 99%

Role of platelet-derived growth factors in physiology and medicine

Andræ¹,

Gallini²,

Betsholtz³

2008

Genes Dev.

2,075

1,898

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Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) have served as prototypes for growth factor and receptor tyrosine kinase function for more than 25 years. Studies of PDGFs and PDGFRs in animal development have revealed roles for PDGFR-␣ signaling in gastrulation and in the development of the cranial and cardiac neural crest, gonads, lung, intestine, skin, CNS, and skeleton. Similarly, roles for PDGFR-␤ signaling have been established in blood vessel formation and early hematopoiesis. PDGF signaling is implicated in a range of diseases. Autocrine activation of PDGF signaling pathways is involved in certain gliomas, sarcomas, and leukemias. Paracrine PDGF signaling is commonly observed in epithelial cancers, where it triggers stromal recruitment and may be involved in epithelial-mesenchymal transition, thereby affecting tumor growth, angiogenesis, invasion, and metastasis. PDGFs drive pathological mesenchymal responses in vascular disorders such as atherosclerosis, restenosis, pulmonary hypertension, and retinal diseases, as well as in fibrotic diseases, including pulmonary fibrosis, liver cirrhosis, scleroderma, glomerulosclerosis, and cardiac fibrosis. We review basic aspects of the PDGF ligands and receptors, their developmental and pathological functions, principles of their pharmacological inhibition, and results using PDGF pathway-inhibitory or stimulatory drugs in preclinical and clinical contexts.Platelet-derived growth factor (PDGF) was identified more than three decades ago as a serum growth factor for fibroblasts, smooth muscle cells (SMCs), and glia cells (Kohler and Lipton 1974;Ross et al. 1974;Westermark and Wasteson 1976). Human PDGF was originally identified as a disulfide-linked dimer of two different polypeptide chains, A and B, separable using reversed phase chromatography (Johnsson et al. 1982). The B-chain (PDGF-B) was characterized by amino acid sequencing, revealing a close homology between PDGF-B and the product of the retroviral oncogene v-sis of simian sarcoma virus (SSV) (Doolittle et al. 1983;Waterfield et al. 1983). Subsequent studies confirmed that the human cellular counterpart (c-sis) was identical to PDGF-B and that autocrine PDGF activity was sufficient for SSV transformation in vitro. This was a paradigm-shifting discovery about the relationship between neoplastic cell transformation and normal growth control. For the first time, the importance of autocrine growth stimulation in neoplastic transformation was demonstrated. As discussed below, it is now well established that autocrine PDGF stimulation plays a role also in some human cancers.PDGF-A was characterized by cDNA cloning ). This resolved a paradoxical lack of correlation between secretion of PDGF-like growth factors from tumor cell lines and their expression of c-sis; it turned out that most such cell lines express PDGF-A and secrete PDGF-AA homodimers ). Together with the demonstration that PDGF-BB homodimers are produced by SSV-transformed or PDGF-Bexpressing cells, these results showed that the PDGF...

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“…18 The slides were examined by 2 independent observers in a blinded review. In the rabbit model, the arteries were divided into 3 categories according to their diameter: large (Ͼ120 m), medium (40 to 120 m), and small (Ͻ40 m).…”

Section: Histologymentioning

confidence: 99%

Vascular Endothelial Growth Factor Enhances Cardiac Allograft Arteriosclerosis

et al. 2002

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Background-Cardiac allograft arteriosclerosis is a complex process of alloimmune response, chronic inflammation, and smooth muscle cell proliferation that includes cross talk between cytokines and growth factors. Methods and Results-Our results in rat cardiac allografts established alloimmune response as an alternative stimulus capable of inducing vascular endothelial growth factor (VEGF) mRNA and protein expression in cardiomyocytes and graft-infiltrating mononuclear inflammatory cells, which suggests that these cells may function as a source of VEGF to the cells of coronary arteries. Linear regression analysis of these allografts with different stages of arteriosclerotic lesions revealed a strong correlation between intragraft VEGF protein expression and the development of intimal thickening, whereas blockade of signaling downstream of VEGF receptor significantly reduced arteriosclerotic lesions. In addition, in cholesterol-fed rabbits, intracoronary perfusion of cardiac allografts with a clinical-grade adenoviral vector that encoded mouse VEGF 164 enhanced the formation of arteriosclerotic lesions, possibly secondary to increased intragraft influx of macrophages and neovascularization in the intimal lesions. Conclusions-Our findings suggest a positive regulatory role between VEGF and coronary arteriosclerotic lesion formation in the allograft cytokine microenvironment.

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Prevention of Cardiac Allograft Arteriosclerosis by Protein Tyrosine Kinase Inhibitor Selective for Platelet-Derived Growth Factor Receptor

Abstract: We conclude that a PDGF-AA/Ralpha-dependent cycle is induced in the generation of allograft arteriosclerosis that may be inhibited by blocking of signaling downstream of PDGF-R.

Cited by 58 publications

References 23 publications

Macrophage Depletion Suppresses Cardiac Allograft Vasculopathy in Mice

Macrophage Depletion Suppresses Cardiac Allograft Vasculopathy in Mice

Role of platelet-derived growth factors in physiology and medicine

Vascular Endothelial Growth Factor Enhances Cardiac Allograft Arteriosclerosis

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