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Biochemical and Immunomorphological Evaluation of Hepatocyte Growth Factor and c-Met Pathway in Patients with Critical Limb Ischemia

Objectives Hepatocyte growth factor (HGF), the c-Met receptor, and hypoxia-inducible factor (HIF) are crucial for regenerative processes including ischemic wound healing. The aims of the present study are (a) to analyze the tissue c-Met and HIF-1α expression in skin from patients with critical limb...

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Published in:European journal of vascular and endovascular surgery 2014-10, Vol.48 (4), p.430-437
Main Authors: Vasuri, F, Fittipaldi, S, Abualhin, M, Degiovanni, A, Gargiulo, M, Stella, A, Pasquinelli, G
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container_title European journal of vascular and endovascular surgery
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creator Vasuri, F
Fittipaldi, S
Abualhin, M
Degiovanni, A
Gargiulo, M
Stella, A
Pasquinelli, G
description Objectives Hepatocyte growth factor (HGF), the c-Met receptor, and hypoxia-inducible factor (HIF) are crucial for regenerative processes including ischemic wound healing. The aims of the present study are (a) to analyze the tissue c-Met and HIF-1α expression in skin from patients with critical limb ischemia (CLI); (b) to compare the serum HGF levels of CLI and control subjects. Methods This is a prospective, controlled, single-center study. Thirty-seven patients were enrolled. A skin sample adjacent to the ischemic lesion was taken from 20 patients with CLI; skin samples were taken from the surgical wounds of 17 patients surgically treated for abdominal aortic aneurysm as healthy controls. Serum samples were taken in all cases. Samples were formalin fixed, paraffin embedded, and routinely processed. Tissue inflammation was histologically assessed. Immunohistochemistry was performed with antibodies against total c-Met receptor, activated Met (p-Met), and HIF-1α. RT-polymerase chain reaction was used to quantify HIF-1α mRNA. The enzyme-linked immunosorbent assay was performed to evaluate serum HGF levels. Results With immunohistochemistry, while total c-Met was unchanged, different patterns of p-Met positivity were observed between CLI and control cases ( p  
doi_str_mv 10.1016/j.ejvs.2014.05.002
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The aims of the present study are (a) to analyze the tissue c-Met and HIF-1α expression in skin from patients with critical limb ischemia (CLI); (b) to compare the serum HGF levels of CLI and control subjects. Methods This is a prospective, controlled, single-center study. Thirty-seven patients were enrolled. A skin sample adjacent to the ischemic lesion was taken from 20 patients with CLI; skin samples were taken from the surgical wounds of 17 patients surgically treated for abdominal aortic aneurysm as healthy controls. Serum samples were taken in all cases. Samples were formalin fixed, paraffin embedded, and routinely processed. Tissue inflammation was histologically assessed. Immunohistochemistry was performed with antibodies against total c-Met receptor, activated Met (p-Met), and HIF-1α. RT-polymerase chain reaction was used to quantify HIF-1α mRNA. The enzyme-linked immunosorbent assay was performed to evaluate serum HGF levels. Results With immunohistochemistry, while total c-Met was unchanged, different patterns of p-Met positivity were observed between CLI and control cases ( p  &lt; .001). In particular, CLI skin showed a total negativity or membrane positivity for p-Met (19/20 cases), while control skin mainly showed cytoplasmic positivity in the epidermal basal layer (16/17 cases). HIF-1α was diffusely lost in CLI, but HIF-1α mRNA was threefold higher than in controls. Finally, mean serum HGF levels were 590.5 pg/mL and 2380.0 pg/mL in CLI and control groups respectively ( p  &lt; .001). Conclusions In CLI patients a significant decrease in serum HGF levels, concomitant with a loss of skin HIF-1α stabilization and a lack of c-Met phosphorylation were seen, probably driving a decrease in wound-healing functions. The next hypothesis is that HGF application might reactivate the c-Met receptor, stabilizing the normal wound healing process.</description><identifier>ISSN: 1078-5884</identifier><identifier>EISSN: 1532-2165</identifier><identifier>DOI: 10.1016/j.ejvs.2014.05.002</identifier><identifier>PMID: 24947080</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Adult ; Aged ; Aged, 80 and over ; Arterial Occlusive Diseases - genetics ; Arterial Occlusive Diseases - metabolism ; Arterial Occlusive Diseases - surgery ; Critical limb ischemia ; DNA - genetics ; Enzyme-Linked Immunosorbent Assay ; Female ; Follow-Up Studies ; Gene Expression Regulation ; Healing time ; Hepatocyte growth factor ; Humans ; Hypoxia inducible factor ; Hypoxia-Inducible Factor 1, alpha Subunit - biosynthesis ; Hypoxia-Inducible Factor 1, alpha Subunit - genetics ; Immunohistochemistry ; Ischemia - genetics ; Ischemia - metabolism ; Ischemia - surgery ; Ischemic lesion ; Leg - blood supply ; Male ; Met receptor ; Middle Aged ; Prospective Studies ; Proto-Oncogene Proteins c-met - biosynthesis ; Proto-Oncogene Proteins c-met - genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Skin - blood supply ; Skin - metabolism ; Skin - pathology ; Surgery ; Vascular Surgical Procedures ; Wound Healing</subject><ispartof>European journal of vascular and endovascular surgery, 2014-10, Vol.48 (4), p.430-437</ispartof><rights>European Society for Vascular Surgery</rights><rights>2014 European Society for Vascular Surgery</rights><rights>Copyright © 2014 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c525t-7b16fbfc80eb03974e7ce57a9aad39353a2ac4ef542900432dc3e0fa3a1c63423</citedby><cites>FETCH-LOGICAL-c525t-7b16fbfc80eb03974e7ce57a9aad39353a2ac4ef542900432dc3e0fa3a1c63423</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24947080$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Vasuri, F</creatorcontrib><creatorcontrib>Fittipaldi, S</creatorcontrib><creatorcontrib>Abualhin, M</creatorcontrib><creatorcontrib>Degiovanni, A</creatorcontrib><creatorcontrib>Gargiulo, M</creatorcontrib><creatorcontrib>Stella, A</creatorcontrib><creatorcontrib>Pasquinelli, G</creatorcontrib><title>Biochemical and Immunomorphological Evaluation of Hepatocyte Growth Factor and c-Met Pathway in Patients with Critical Limb Ischemia</title><title>European journal of vascular and endovascular surgery</title><addtitle>Eur J Vasc Endovasc Surg</addtitle><description>Objectives Hepatocyte growth factor (HGF), the c-Met receptor, and hypoxia-inducible factor (HIF) are crucial for regenerative processes including ischemic wound healing. The aims of the present study are (a) to analyze the tissue c-Met and HIF-1α expression in skin from patients with critical limb ischemia (CLI); (b) to compare the serum HGF levels of CLI and control subjects. Methods This is a prospective, controlled, single-center study. Thirty-seven patients were enrolled. A skin sample adjacent to the ischemic lesion was taken from 20 patients with CLI; skin samples were taken from the surgical wounds of 17 patients surgically treated for abdominal aortic aneurysm as healthy controls. Serum samples were taken in all cases. Samples were formalin fixed, paraffin embedded, and routinely processed. Tissue inflammation was histologically assessed. Immunohistochemistry was performed with antibodies against total c-Met receptor, activated Met (p-Met), and HIF-1α. RT-polymerase chain reaction was used to quantify HIF-1α mRNA. The enzyme-linked immunosorbent assay was performed to evaluate serum HGF levels. Results With immunohistochemistry, while total c-Met was unchanged, different patterns of p-Met positivity were observed between CLI and control cases ( p  &lt; .001). In particular, CLI skin showed a total negativity or membrane positivity for p-Met (19/20 cases), while control skin mainly showed cytoplasmic positivity in the epidermal basal layer (16/17 cases). HIF-1α was diffusely lost in CLI, but HIF-1α mRNA was threefold higher than in controls. Finally, mean serum HGF levels were 590.5 pg/mL and 2380.0 pg/mL in CLI and control groups respectively ( p  &lt; .001). Conclusions In CLI patients a significant decrease in serum HGF levels, concomitant with a loss of skin HIF-1α stabilization and a lack of c-Met phosphorylation were seen, probably driving a decrease in wound-healing functions. The next hypothesis is that HGF application might reactivate the c-Met receptor, stabilizing the normal wound healing process.</description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Arterial Occlusive Diseases - genetics</subject><subject>Arterial Occlusive Diseases - metabolism</subject><subject>Arterial Occlusive Diseases - surgery</subject><subject>Critical limb ischemia</subject><subject>DNA - genetics</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Female</subject><subject>Follow-Up Studies</subject><subject>Gene Expression Regulation</subject><subject>Healing time</subject><subject>Hepatocyte growth factor</subject><subject>Humans</subject><subject>Hypoxia inducible factor</subject><subject>Hypoxia-Inducible Factor 1, alpha Subunit - biosynthesis</subject><subject>Hypoxia-Inducible Factor 1, alpha Subunit - genetics</subject><subject>Immunohistochemistry</subject><subject>Ischemia - genetics</subject><subject>Ischemia - metabolism</subject><subject>Ischemia - surgery</subject><subject>Ischemic lesion</subject><subject>Leg - blood supply</subject><subject>Male</subject><subject>Met receptor</subject><subject>Middle Aged</subject><subject>Prospective Studies</subject><subject>Proto-Oncogene Proteins c-met - biosynthesis</subject><subject>Proto-Oncogene Proteins c-met - genetics</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Skin - blood supply</subject><subject>Skin - metabolism</subject><subject>Skin - pathology</subject><subject>Surgery</subject><subject>Vascular Surgical Procedures</subject><subject>Wound Healing</subject><issn>1078-5884</issn><issn>1532-2165</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><recordid>eNp9kU2P0zAQhiMEYpeFP8AB5cgl2fFXPiSEBNV-VCoCCThbjjOhDklcbKdV7_xwnHaXAwdOHlnv-87MM0nymkBOgBTXfY793ucUCM9B5AD0SXJJBKMZJYV4Gmsoq0xUFb9IXnjfA4AgTDxPLiiveQkVXCa_PxqrtzgarYZUTW26Hsd5sqN1u60d7I_T_81eDbMKxk6p7dJ73Klg9TFgeufsIWzTW6WDdSe7zj5hSL-osD2oY2qmpTQ4BZ8eTFSunAmnyI0Zm3TtT63Vy-RZpwaPrx7eq-T77c231X22-Xy3Xn3YZFpQEbKyIUXXdLoCbIDVJcdSoyhVrVTLaiaYokpz7ASnNQBntNUMoVNMEV0wTtlV8vacu3P214w-yNF4jcOgJrSzl0QUBYeK8SJK6VmqnfXeYSd3zozKHSUBudCXvVzoy4W-BCEj_Wh685A_NyO2fy2PuKPg3VmAccu9QSe9jnQ0tsahDrK15v_57_-x68FMC8-feETf29lNkZ8k0lMJ8uty_-X8hEd3nIH9AWzrrLc</recordid><startdate>20141001</startdate><enddate>20141001</enddate><creator>Vasuri, F</creator><creator>Fittipaldi, S</creator><creator>Abualhin, M</creator><creator>Degiovanni, A</creator><creator>Gargiulo, M</creator><creator>Stella, A</creator><creator>Pasquinelli, G</creator><general>Elsevier Ltd</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20141001</creationdate><title>Biochemical and Immunomorphological Evaluation of Hepatocyte Growth Factor and c-Met Pathway in Patients with Critical Limb Ischemia</title><author>Vasuri, F ; Fittipaldi, S ; Abualhin, M ; Degiovanni, A ; Gargiulo, M ; Stella, A ; Pasquinelli, G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c525t-7b16fbfc80eb03974e7ce57a9aad39353a2ac4ef542900432dc3e0fa3a1c63423</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Arterial Occlusive Diseases - genetics</topic><topic>Arterial Occlusive Diseases - metabolism</topic><topic>Arterial Occlusive Diseases - surgery</topic><topic>Critical limb ischemia</topic><topic>DNA - genetics</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>Female</topic><topic>Follow-Up Studies</topic><topic>Gene Expression Regulation</topic><topic>Healing time</topic><topic>Hepatocyte growth factor</topic><topic>Humans</topic><topic>Hypoxia inducible factor</topic><topic>Hypoxia-Inducible Factor 1, alpha Subunit - biosynthesis</topic><topic>Hypoxia-Inducible Factor 1, alpha Subunit - genetics</topic><topic>Immunohistochemistry</topic><topic>Ischemia - genetics</topic><topic>Ischemia - metabolism</topic><topic>Ischemia - surgery</topic><topic>Ischemic lesion</topic><topic>Leg - blood supply</topic><topic>Male</topic><topic>Met receptor</topic><topic>Middle Aged</topic><topic>Prospective Studies</topic><topic>Proto-Oncogene Proteins c-met - biosynthesis</topic><topic>Proto-Oncogene Proteins c-met - genetics</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>Skin - blood supply</topic><topic>Skin - metabolism</topic><topic>Skin - pathology</topic><topic>Surgery</topic><topic>Vascular Surgical Procedures</topic><topic>Wound Healing</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Vasuri, F</creatorcontrib><creatorcontrib>Fittipaldi, S</creatorcontrib><creatorcontrib>Abualhin, M</creatorcontrib><creatorcontrib>Degiovanni, A</creatorcontrib><creatorcontrib>Gargiulo, M</creatorcontrib><creatorcontrib>Stella, A</creatorcontrib><creatorcontrib>Pasquinelli, G</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of vascular and endovascular surgery</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Vasuri, F</au><au>Fittipaldi, S</au><au>Abualhin, M</au><au>Degiovanni, A</au><au>Gargiulo, M</au><au>Stella, A</au><au>Pasquinelli, G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Biochemical and Immunomorphological Evaluation of Hepatocyte Growth Factor and c-Met Pathway in Patients with Critical Limb Ischemia</atitle><jtitle>European journal of vascular and endovascular surgery</jtitle><addtitle>Eur J Vasc Endovasc Surg</addtitle><date>2014-10-01</date><risdate>2014</risdate><volume>48</volume><issue>4</issue><spage>430</spage><epage>437</epage><pages>430-437</pages><issn>1078-5884</issn><eissn>1532-2165</eissn><abstract>Objectives Hepatocyte growth factor (HGF), the c-Met receptor, and hypoxia-inducible factor (HIF) are crucial for regenerative processes including ischemic wound healing. The aims of the present study are (a) to analyze the tissue c-Met and HIF-1α expression in skin from patients with critical limb ischemia (CLI); (b) to compare the serum HGF levels of CLI and control subjects. Methods This is a prospective, controlled, single-center study. Thirty-seven patients were enrolled. A skin sample adjacent to the ischemic lesion was taken from 20 patients with CLI; skin samples were taken from the surgical wounds of 17 patients surgically treated for abdominal aortic aneurysm as healthy controls. Serum samples were taken in all cases. Samples were formalin fixed, paraffin embedded, and routinely processed. Tissue inflammation was histologically assessed. Immunohistochemistry was performed with antibodies against total c-Met receptor, activated Met (p-Met), and HIF-1α. RT-polymerase chain reaction was used to quantify HIF-1α mRNA. The enzyme-linked immunosorbent assay was performed to evaluate serum HGF levels. Results With immunohistochemistry, while total c-Met was unchanged, different patterns of p-Met positivity were observed between CLI and control cases ( p  &lt; .001). In particular, CLI skin showed a total negativity or membrane positivity for p-Met (19/20 cases), while control skin mainly showed cytoplasmic positivity in the epidermal basal layer (16/17 cases). HIF-1α was diffusely lost in CLI, but HIF-1α mRNA was threefold higher than in controls. Finally, mean serum HGF levels were 590.5 pg/mL and 2380.0 pg/mL in CLI and control groups respectively ( p  &lt; .001). Conclusions In CLI patients a significant decrease in serum HGF levels, concomitant with a loss of skin HIF-1α stabilization and a lack of c-Met phosphorylation were seen, probably driving a decrease in wound-healing functions. The next hypothesis is that HGF application might reactivate the c-Met receptor, stabilizing the normal wound healing process.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>24947080</pmid><doi>10.1016/j.ejvs.2014.05.002</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record>
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ispartof European journal of vascular and endovascular surgery, 2014-10, Vol.48 (4), p.430-437
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subjects Adult
Aged
Aged, 80 and over
Arterial Occlusive Diseases - genetics
Arterial Occlusive Diseases - metabolism
Arterial Occlusive Diseases - surgery
Critical limb ischemia
DNA - genetics
Enzyme-Linked Immunosorbent Assay
Female
Follow-Up Studies
Gene Expression Regulation
Healing time
Hepatocyte growth factor
Humans
Hypoxia inducible factor
Hypoxia-Inducible Factor 1, alpha Subunit - biosynthesis
Hypoxia-Inducible Factor 1, alpha Subunit - genetics
Immunohistochemistry
Ischemia - genetics
Ischemia - metabolism
Ischemia - surgery
Ischemic lesion
Leg - blood supply
Male
Met receptor
Middle Aged
Prospective Studies
Proto-Oncogene Proteins c-met - biosynthesis
Proto-Oncogene Proteins c-met - genetics
Reverse Transcriptase Polymerase Chain Reaction
Skin - blood supply
Skin - metabolism
Skin - pathology
Surgery
Vascular Surgical Procedures
Wound Healing
title Biochemical and Immunomorphological Evaluation of Hepatocyte Growth Factor and c-Met Pathway in Patients with Critical Limb Ischemia
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