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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 7 2425-2428
Copyright © 1999 by The Endocrine Society

Original Studies

Serum Hepatocyte Growth Factor in Patients with Peripheral Arterial Occlusive Disease

Yuji Yoshitomi, Shunichi Kojima, Takuya Umemoto, Kiyokage Kubo, Yuji Matsumoto, Michiko Yano, Toshihiko Sugi and Morio Kuramochi

Division of Cardiology (Y.Y., Y.M., M.Y., T.S., M.K.), Department of Clinical Research (S.K.), Division of Cardiovascular Surgery (T.U., K.K.), Tohsei National Hospital, Shizuoka 411, Japan

Address all correspondence and requests for reprints to: Yuji Yoshitomi, M.D., Division of Cardiology, Tohsei National Hospital, 762–1 Nagasawa, Shimizu-cho, Suntoh-gun, Shizuoka 411, Japan. E-mail: yyoshito{at}jun.ncvc.go.jp


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Hepatocyte growth factor (HGF) is a multifunctional protein implicated in tissue regeneration, wound healing, and angiogenesis. We measured serum HGF concentrations in 37 patients with peripheral arterial occlusive disease (PAOD). Among them, 36 patients underwent arteriography. Serum HGF concentrations were also measured in 40 control subjects who remained free of vascular, liver, kidney, or lung disease. Patients with PAOD showed elevated serum HGF concentrations compared with control subjects (0.40 ± 0.02 vs. 0.19 ± 0.01 ng/mL; P < 0.001). Serum HGF concentrations were significantly higher in smokers compared with nonsmokers (0.45 ± 0.03 vs. 0.35 ± 0.02 ng/mL; P = 0.003). The serum HGF concentrations in patients with collaterals tended to be higher than those in patients without collaterals (0.43 ± 0.03 vs. 0.35 ± 0.02 ng/mL; P = 0.06). Moreover, in patients who underwent bypass surgery or angioplasty, serum HGF concentrations decreased from 0.41 ± 0.03 to 0.21 ± 0.04 ng/mL after treatment (P < 0.001). Serum HGF may be an useful marker for the diagnosis of PAOD. HGF may play an important role in angiogenesis and collateral vessel growth in PAOD.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
HEPATOCYTE growth factor (HGF) was first identified in the sera of partially hepatectomized rats as a potent mitogen for mature hepatocytes (1, 2), and it was later isolated from human serum (3). HGF seems to function as an organotropic factor for regeneration of various organs, including liver, kidney, and lung (4, 5, 6, 7). Recent findings concerning HGF indicate that HGF is a mesenchymal-derived pleiotropic factor that regulates cell growth, cell motility, and morphogenesis of various types of cells (4). In 1993, it was demonstrated that HGF exhibits angiogenic activities in vivo, suggesting an important role during ischemic damage (8). Recently, circulating HGF may be related to neovascularization in proliferative diabetic retinopathy (9). Clinical study demonstrated a possibility that serum HGF secretion is elevated in response to high blood pressure as a countersystem against endothelial dysfunction (10). However, there has been no report of serum HGF concentrations in patients with atherosclerotic peripheral arterial occlusive disease (PAOD) who have obvious atherosclerosis and endothelial dysfunction. We therefore sought to estimate pathophysiological significance of HGF in patients with PAOD without liver, kidney, or lung disease.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
We studied 37 patients with PAOD: 29 men and 8 women (46–85 yr old; mean ± SEM, 69 ± 2 yr). We excluded patients with liver, kidney, or lung disease. The diagnosis of PAOD was based on patient history and clinical examination, with ankle-brachial pressure index (ABI) of 0.8 or less. The average time from onset of symptoms to admission was 3.7 ± 0.9 months (range, 1.5–10 months). No patients showed acute thrombosis of peripheral arteries. Arteriography was performed in 95% of patients. The patients were divided into 2 distinct classes according to the severity of ischemic symptoms: intermittent claudication (group I) and critical ischemia (rest pain, skin lesions, or gangrene; group II). Patients were further stratified into 2 subgroups according to whether total or subtotal occlusion was associated with collaterals or without collaterals by arteriography. Patients were also divided into 2 groups, 1 with serum HGF concentrations above the group median and the other with serum HGF levels below the group median. Serum HGF concentrations were also measured in 40 control subjects (43–77 yr old; mean age, 66 ± 2 yr) who remained free of vascular, liver, kidney, and lung disease. All patients gave their informed consent to participate in the study. The study was approved by our institutional review board on clinical study.

Risk factors, which were reviewed from the hospital records, included age, resting blood pressure, serum cholesterol, smoking, and presence of diabetes mellitus. Angina pectoris, myocardial infarction, cerebral infarction, or bleeding were diagnosed by patient history, electrocardiogram, computed tomography, and arteriography. Aortic aneurysm was diagnosed by computed tomography or aortography. Complication included coronary artery disease (angina pectoris and myocardial infarction) and cerebral infarction or bleeding.

Twenty-four patients underwent bypass surgery, and 5 patients underwent percutaneous transluminal angioplasty (PTA). According to serum HGF concentrations after surgery or PTA, the patients were classified into 2 groups: normalized and unchanged. The PGI2 analog (beraprost sodium) alone was administered to 4 patients, and PGE1 alone was given to 3 patients. Antihypertensive agents were administered to 86% of patients with hypertension. Calcium antagonists were administered to 15 patients, angiotensin-converting enzyme inhibitors to 4 patients, and ß-blockers to 2 patients.

Blood was collected after they had remained supine for at least 30 min early in the morning. Blood was centrifuged, and the separated serum was stored at -80 C until assay. Serum HGF concentrations were measured by solid phase enzyme-linked immunosorbent assay for use in humans using kits developed by Otsuka Assay Laboratories (Otsuka Pharmaceutical Co., Tokyo, Japan) (11). The intra- and interassay variations were 2.9% and 2.6%, respectively (11). The sensitivity of the kits was 0.10 ng/mL.

Statistical methods

Data are expressed as the mean ± SEM. Serum HGF concentrations were compared using paired or unpaired Student’s t test. Correlations between serum HGF concentrations, and ABI and blood pressure were analyzed by linear regression analysis. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Patient characteristics

Clinical characteristics are shown in Table 1Go. Only 1 patient revealed no risk factors. Sixteen patients revealed no complications. Among patients who were treated with antihypertensive drugs, 10 showed blood pressure over 140/90 mm Hg. Forty-three percent of patients with collaterals revealed critical ischemia.


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  		Table 1. Clinical characteristics

 
Serum HGF concentration in PAOD

The mean serum HGF concentration in the control subjects was 0.19 ± 0.02 ng/mL. In contrast, patients with PAOD showed elevated serum HGF concentrations (0.40 ± 0.02 ng/mL; P < 0.001; Fig. 1Go). The serum HGF concentrations did not correlate with ABI (r = 0.36; P = NS). There was no significant difference in serum HGF concentrations between group I and group II [0.38 ± 0.02 ng/mL (n = 22) vs. 0.43 ± 0.03 ng/mL (n = 14); P = NS]. However, serum HGF concentrations in patients with collaterals tended to be higher than those in patients without collaterals (0.43 ± 0.03 vs. 0.35 ± 0.02 ng/mL; P = 0.06). There was no significant difference in serum HGF concentrations between patients with collaterals and those without collaterals in the both groups [group I, 0.41 ± 0.03 ng/mL (n = 13) vs. 0.34 ± 0.04 ng/mL (n = 9); group II, 0.45 ± 0.04 ng/mL (n = 10) vs. 0.39 ± 0.04 ng/mL (n = 4); P = NS]. Among patients who underwent successful bypass surgery or PTA, follow-up serum HGF concentrations were measured in 20 patients (mean follow-up, 6.2 ± 0.6 months). Serum HGF concentrations decreased after treatment (before, 0.41 ± 0.03 ng/mL; after, 0.21 ± 0.04 ng/mL; P < 0.001; Fig. 2Go). There were no significant differences in risk factors, complications, or medications between the normalized group and the unchanged group.



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  		Figure 1. Serum HGF concentrations in control subjects (n = 40) and patients with PAOD (n = 37). Among patients with PAOD, open circles indicate patients without complications (n = 16). Closed circles indicate patients with complications (n = 21). The open triangle indicates a patient without risk factors and complications.

 


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  		Figure 2. Serum HGF concentrations before and after treatment in patients who underwent bypass surgery or percutaneous transluminal angioplasty (n = 20).

 
There was no significant difference in serum HGF concentrations between patients treated with PGI2 or PGE1 and those not treated [0.45 ± 0.06 ng/mL (n = 7) vs. 0.39 ± 0.02 ng/mL (n = 30); P = NS].

Risk factors and serum HGF

Correlations between risk factors and serum HGF concentrations are shown in Table 2Go. There were no significant differences in serum HGF concentrations between patients with and without risk factors, such as hypertension, diabetes mellitus, and hypercholesterolemia. Among control subjects, serum HGF concentrations did not differ between smokers and nonsmokers (0.19 ± 0.01 vs. 0.18 ± 0.01 ng/mL; P = NS). In patients with PAOD, however, serum HGF concentrations were significantly higher in smokers compared with nonsmokers (0.45 ± 0.03 vs. 0.35 ± 0.02 ng/mL; P = 0.003). Smoking was more prevalent in the subgroup of PAOD patients with conditions above the group median than in the subgroup below the group median (78% vs. 32%; P < 0.01). There were not significant correlations between serum HGF concentrations and blood pressure (systolic blood pressure, r = 0.29; diastolic blood pressure, r = 0.11; P = NS). Among patients complicated by hypertension, there was no significant difference in serum HGF concentrations between patients with blood pressure over 140/90 mm Hg and those with blood pressure under 140/90 mm Hg (0.38 ± 0.02 vs. 0.40 ± 0.04 ng/mL; P = NS). Complications such as coronary artery disease and cerebral infarction or bleeding did not affect serum HGF concentrations. There were no significant differences in risk factors, complications, or medications between patients with and without coronary artery disease or between patients with and without hypercholesterolemia.


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  		Table 2. Serum HGF concentrations in risk factors and complications

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In our study, the circulating HGF concentrations were higher in patients with PAOD than in control subjects and decreased after interventional treatment. The serum HGF concentration did not always reflect the severity of ischemia. Several reports suggested that circulating HGF rises dependent on the severity of hypertension and in response to high blood pressure as a counterregulatory system against endothelial dysfunction (10, 12). A decrease in circulating HGF after interventional treatment suggests that elevation of circulating HGF may play an important role in angiogenesis rather than in protection against endothelial dysfunction, as in hypertensive patients.

HGF stimulates vascular endothelial cell migration, proliferation, and organization into capillary-like tubes in vitro (13). Recently, vascular endothelial growth factor, known as a potent mitogenic for endothelial cells, has been used for gene therapy of angiogenesis in patients with PAOD (14). Thus, it is possible that HGF also promotes angiogenesis to compensate for severe ischemia in patients with PAOD. Recombinant human HGF induced angiogenesis in vivo (8). Furthermore, Ono et al. suggested that HGF plays a significant role in angiogenesis and collateral vessel growth in a rat model of myocardial ischemia (15). HGF may play an important role in collateral vessel growth in PAOD. This characteristic of HGF as angiogenesis may provide the opportunity for a new therapeutic strategy for PAOD. Further studies are needed to determine the exact effect of angiogenesis of HGF in patients with PAOD.

The serum HGF concentration has recently been reported to be increased in arterial thrombosis (15, 16, 17). In patients with acute myocardial infarction, serum HGF concentrations increased within 3 h after the onset of chest pain (16). Measurements of circulating HGF may be useful in the early diagnosis of arterial thrombosis. In our study, however, no patients revealed acute thrombosis of peripheral arteries. Thus, circulating HGF may also be a useful marker in chronic phase of PAOD.

The source of circulating HGF was not determined in this study. In the rat, HGF messenger ribonucleic acid is expressed in the liver and a number of other organs, including the kidney, lung, and spleen (18). One of the candidates for HGF release is vascular tissue affected by atherosclerosis (19). However, an experimental study suggested that decreased local HGF production in blood vessels may have been related to the development of atherosclerosis (20). Previous studies suggested that HGF messenger ribonucleic acid in the intact lung or kidney markedly increased after partial hepatectomy or unilateral nephrectomy in rats (21, 22). These results suggested that the onset of injury to the liver or kidney may be recognized by distal noninjured organs via the signaling of a humoral factor and that HGF derived from these organs may be involved in the regeneration of liver or kidney, through an endocrine mechanism. Therefore, HGF may be produced in extravascular tissues or organs, such as the liver, kidney, lung, and spleen, and/or against decreased local HGF due to atherosclerosis in PAOD.

Cytokines, such as interleukin-1 and tumor necrosis factor-{alpha}, stimulate HGF production (23). Because elevated levels of tumor necrosis factor-{alpha} and interleukin-1 have been reported in sera from patients with fluminant hepatic failure, these cytokines may regulate HGF expression in liver disease (24). Circulating cytokines, such as interleukin-1 and tumor necrosis factor-{alpha}, were increased in patients with PAOD (25). Thus, cytokines may relate to the production of HGF.

Interestingly, serum HGF concentrations in smokers with PAOD were significantly higher compared with those in nonsmokers. Recently, serum HGF concentrations in current smokers were significantly higher than those in nonsmokers in patients with pulmonary fibrosis (26). Although smoking is related to atherosclerotic disease, little is known about the underlying mechanisms. The association between smoking and PAOD may, in fact, be even stronger than that between smoking and coronary heart disease (27). As there was a difference in the effect of smoking between PAOD and control subjects, smoking may have an additional effect on circulating HGF in PAOD.

PG derivatives, often employed as a painkiller for severe symptoms of PAOD, have been shown to stimulate HGF production from human aortic smooth muscle cells and human skin fibroblasts (28, 29). In the present study, however, serum HGF concentrations did not differ significantly between patients treated with PGs and those not treated. PGs do not seem to affect circulating HGF.

We found no correlation between serum HGF concentrations and blood pressure. This finding differs from that of a previous study by Nakamura et al. (10). The discrepancy may be ascribed to therapy with antihypertensive agents in patients complicated by hypertension. Recent report suggests that hypertensive patients treated with antihypertensive drugs showed the same levels of serum HGF as normotensive subjects (12). Although blood pressure was decreased by antihypertensive therapy, our patients showed increased serum HGF concentrations. Other factors may be related to regulation of HGF production in PAOD.

In conclusion, our data demonstrate that circulating HGF increases in patients with PAOD and decreases after bypass surgery or angioplasty. Thus, HGF may serve as a marker for PAOD. Circulating HGF may play an important role in collateral vessel growth.


   Acknowledgments
 
We are indebted to Ms. Hiromi Hosaka for secretarial assistance.

Received November 16, 1998.

Revised February 8, 1999.

Revised March 24, 1999.

Accepted March 29, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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