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Endocrinology Vol. 145, No. 11 4934-4939
Copyright © 2004 by The Endocrine Society

Influence of Diabetes on the Exacerbation of an Inflammatory Response in Cardiovascular Tissue

Huafei Lu, Markos Raptis, Elena Black, Maria Stan, Salomon Amar and Dana T. Graves

Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, Massachusetts 02118

Address all correspondence and requests for reprints to: Dana T. Graves, Boston University School of Dental Medicine, W-202D, 700 Albany Street, Boston, Massachusetts 02118. E-mail: dgraves{at}bu.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Coronary artery disease results from an inflammatory process in blood vessels of afflicted individuals. This process is accelerated with diabetes for reasons that are largely unknown. Recent evidence indicates that infection at sites remote from the heart leads to bacteremia and endotoxemia, thereby stimulating systemic inflammation, which represents an important risk factor for atherosclerosis. We examined the inflammatory response of the heart/aorta of diabetic db/db mice that develop type II diabetes. Subcutaneous inoculation of lipopolysaccharide was used to mimic a local infection. This stimulated an up-regulation of adhesion molecules, cytokines, and chemokines via an endotoxemia that was significantly more rapid and more pronounced in the diabetic compared with normal mice. The 13- to 30-fold induction of key proinflammatory molecules in the heart/aorta of diabetic mice even exceeded that at the site of inoculation. Given that infection, bacteremia, and endotoxemia are relatively frequent events in humans, these results identify a putative mechanism for increased cardiovascular heart disease in diabetes.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
DIABETES MELLITUS AFFECTS more than 16 million people in the United States (1). Type I and type II diabetics develop atherosclerosis much earlier in life and at an accelerated rate compared with their nondiabetic cohorts (2). Morbidity and mortality caused by coronary vascular disease is two times higher in male and three times higher in female diabetic patients (3). Moreover, 80% of type II diabetic individuals die from coronary artery disease (4).

The inflammatory process plays a key role in coronary artery disease initiation, progression, and complication. One of the best studied of the inflammatory stimuli is oxidized low-density lipoprotein (5). However, it is likely that other mediators are also involved, some of which may be of infectious origin (6). This point is strongly reinforced by findings that markers of systemic inflammation such as serum levels of C-reactive protein and TNF-{alpha} represent significant risk factors for atherosclerosis (7).

The inflammatory response in large vessels involves the up-regulation of vascular adhesion molecules such as vascular cell adhesion molecule (VCAM)-1 and E-selectin and inflammatory cytokines such as TNF, IL-1, or IL-6 (8). These mediators amplify the inflammatory response, in part, by stimulating the expression of chemokines such as monocyte chemotactic protein 1 and macrophage inflammatory protein (MIP)-1{alpha} that direct the migration of leukocytes into the vessel wall. It is noteworthy that inhibiting the activity of proinflammatory molecules prevents the early steps in atherogenesis (9). Inflammation can also contribute significantly to the development of atherosclerotic lesions by promoting the progression from early lesions to culprit lesions that cause morbidity. This may occur through several mechanisms, including erosion of the plaque surface, stimulation of angiogenesis with subsequent microhemorrhage within the plaque, and enhanced thrombus formation (10). Systemic conditions also play an important role in exacerbating atherogenesis, such as hypertension and diabetes (11, 12).

Recent studies point to the possibility that microbial infections are an important risk factor for cardiovascular diseases (13). Anaerobic bacteria, such as Chlamydia pneumoniae, cause respiratory tract infections and are associated with enhanced rates of atherosclerosis (14). Furthermore, Gram-negative pathogens associated with periodontal disease have also been linked to atherosclerotic plaque formation (15). In this regard, it is thought that periodontal disease can lead frequently to bacteremia, thereby inducing a systemic inflammatory response (16). Finally, Helicobacter pylori cause gastritis and may enhance the incidence of atherosclerotic cardiovascular diseases (17). Animal studies, particularly in rodents, also provide support for the concept that systemic infection significantly aggravates the formation of early atherosclerotic lesions (13, 18). In studies presented below, we report that endotoxemia causes a strong induction of proinflammatory molecules in the heart/aorta and that this is dramatically increased by diabetes. This is the first report that diabetes significantly affects cardiovascular tissue in response to endotoxemia.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
All experimental procedures on animals were performed under the regulations of the Institutional Animal Care and Use Committee (IACUC). Female diabetic db/db mice on C57BKS background and matched db/+ normoglycemic female littermates (Jackson Laboratory, Bar Harbor, ME) were housed in the Laboratory Animal Science Center (LASC) at Boston University Medical Campus. Mice were fed a Tecklad diet no. 2018. The db/db mice, which lack the leptin receptor, develop diabetes at approximately 6–8 wk of age. Experiments were performed at age 11 wk. Mice were considered to be diabetic when the blood glucose level exceeded 250 mg/dl. Blood glucose was always under 150 mg/dl for the control group. Blood glycated hemoglobin levels were measured at the time of death using a Glyco-Affinn GHb test (Perkin-Elmer Life Sciences, Norton, OH). Glycated hemoglobin for normal mice was 2–4%, whereas for the diabetic mice it was 12–15%. Experiments were performed three times with two animals per data point. Tissue specimens were then pooled so that the final number of animals per data point was six (n = 6). Each assay was carried out at least three separate times. Statistical differences between control and diabetic groups were determined by Student’s t test.

Collection of blood and tissue
To mimic a local infection, Escherichia coli lipopolysaccharide (LPS), 50 or 200 µg (List Biological Laboratories, Campbell, CA) was injected sc into the scalp of diabetic and normoglycemic mice. LPS was suspended in sterile PBS by sonication, and 50 µl was injected at the midpoint of the scalp. After injection at the indicated time points, animals were killed, and tissues were collected and immediately frozen in liquid nitrogen. The heart and aorta were cut open and then thoroughly rinsed in sterile PBS before freezing. To obtain blood, cardiac puncture was performed just before killing.

Measurement of plasma TNF-{alpha} and endotoxin
The blood was collected in heparinized endotoxin-free tubes and centrifuged (3500 rpm) for measurement of endotoxin. Serum TNF-{alpha} was measured by ELISA (R&D Systems, Minneapolis, MN), and plasma endotoxin was measured by Pyrochrome Limulus amebocyte lysate (LAL) assay (Associates of Cape Cod, Inc., Woods Hole, MA). Before the LAL assay, plasma was boiled for 2 min according to the manufacturer’s instructions.

Measurement of VCAM-1 in heart/aorta
Protein was extracted from pulverized tissue in the presence of protease inhibitors using a protein extraction kit from Pierce (Rockford, IL). VCAM-1 was measured by ELISA (R&D Systems) with 300 µg protein extract tested per well.

RNA analysis
Total RNA from the scalp and heart/aorta was extracted using Trizol Reagent (Life Technologies Inc., Rockville, MD). Gene expression was measured by the RNase protection assay. P32-labeled RNA probes were generated using a template set from PharMingen (BD Bioscience, Franklin Lakes, NJ) and incubated with 8 µg total RNA to assess changes in mRNA levels of proinflammatory molecules. Samples were subjected to RNase digestion using a kit from PharMingen according to the manufacturer’s instructions. After electrophoresis on 6% polyacrylamide gels, radiolabeled bands were visualized with a PhosphoImager (Bio-Rad Laboratories, Hercules, CA). The optical density of the protected bands was measured with Image ProPlus software (Media Cybernetics, Silver Spring, MD), which was then normalized by the value of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the same lane. The mean densitometric values and SE from three separate RNase protection assays are shown.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Local infection by Gram-negative bacteria can stimulate a systemic response by causing an endotoxemia. In the present studies, we mimicked a local infection by sc injection of LPS and examined the effect on a distant site, the heart/aorta. The goal of these studies was to determine whether diabetes modified the inflammatory response in the cardiovascular tissue in a way that could potentially aggravate atherosclerosis. Experiments were undertaken to measure the response of cardiovascular tissue to local injection of LPS (50 µg) in the scalp. At 12 h, there was a sharply enhanced expression of the proinflammatory molecules IL-1, IL-6, and MIP-2, which have been associated with inflammation-associated atherogenesis (Fig. 1AGo). Most striking is the significantly higher levels of expression achieved in the diabetic vs. the normoglycemic group. At 12 h, there was a 7.1-fold increase in IL-1 mRNA levels in the diabetic vs. a 2.4-fold increase in the normoglycemic controls. For MIP-2 the difference was 9.1-fold in the diabetic compared with 3.8-fold for the controls, and for IL-6 it was 4.5-fold for the diabetic and 2.4-fold for the normal mice. This was followed at 36 h with down-regulation of these inflammatory cytokines. The plasma levels of endotoxin was measured and reached high levels at 12 h and was significantly reduced at 36 h, following a similar pattern as that observed for changes in gene expression (Fig. 1BGo). There was no difference in endotoxin levels in the diabetic and normoglycemic mice.



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  		FIG. 1. Diabetes greatly enhances the expression of IL-1ß, IL-6, and MIP-2 in the heart/aorta in response to local sc injection of LPS. A, Subcutaneous injection of LPS (50 µg) was made into the scalp of diabetic (db/db) mice ({blacksquare}) and normoglycemic littermates ({cjs2108}). RNA levels of each molecule were assessed by RPAs. The resulting autoradiograms and densitometric values normalized by GAPDH levels in the same lane are shown for diabetic (D) and control (C) mice. The control and diabetic mice were significantly different for each cytokine at 12 h and for IL-1ß at 36 h (P < 0.05). Each value represents the mean of three separate RPAs ± SEM and is shown as percent maximum expression. B, Plasma endotoxin activity was measured by a colorimetric LAL assay for control ({cjs2108}) and diabetic ({blacksquare}) mice at 0, 12, and 36 h. Each value represents the mean of three separate assays ± SEM. There was no difference between control and diabetic groups at any time point.

 
In the experiments that followed, 200 µg LPS was inoculated into the scalp, concentrating on early responses. In Fig. 2Go, the expression of the adhesion molecule VCAM-1, which is found on activated endothelial cells, was measured at the protein level. At baseline and 90 min after LPS inoculation, both the diabetic and normal animals expressed equivalent low levels. At 6 h, VCAM-1 had increased 9-fold in the diabetic mice, whereas it was induced only 3-fold in the normal group. At 24 h, the values were similar in the diabetic and normoglycemic mice.



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  		FIG. 2. Diabetes significantly increases VCAM-1 protein levels in the heart and aorta. LPS (200 µg) was injected sc into the scalp of diabetic db/db (D) and control normoglycemic littermates (C). VCAM-1 was measured by ELISA in protein extracted from heart/aorta; 300 µg of total protein was examined per well. Each value represents the mean of four separate ELISAs ± SEM. The control and diabetic groups were significantly different at 6 h (P < 0.05).

 
In the next series of experiments, the expression of endothelial-specific adhesion molecules, chemokines, and cytokines was measured at the mRNA level in specimens from the heart and aorta (Fig. 3Go). Because the expression of endothelial-specific adhesion molecules is a required initial step in inflammation, VCAM-1 and E-selectin were examined. At 90 min, VCAM-1 expression increased 6-fold in the diabetic and 2-fold in the normal mice (Fig. 3AGo). For E-selectin there was a 20-fold induction in the diabetic mice compared with a 5-fold increase in the normal group. At 6 h, both reached maximum levels with the diabetics being significantly higher than the controls (Fig. 3AGo).



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  		FIG. 3. Diabetes greatly enhances the expression of VCAM-1, E-selectin, TNF-{alpha}, IL-1ß, MIP-2, and MIP-1{alpha} in the heart/aorta in response to local sc injection of LPS. Subcutaneous injection of LPS (200 µg) was made into the scalp of diabetic (db/db) ({blacksquare}) and normal littermate control ({cjs2108}) mice. RNA levels of each molecule were assessed by RPAs. The resulting autoradiograms and densitometric values normalized by GAPDH levels in the same lane are shown for diabetic (D) and control (C) animals. Each value represents the mean of three separate RPAs ± SEM and is shown as percent maximum expression. A, Adhesion molecules in the heart/aorta. The control and diabetic groups were significantly different for E-selectin at 1.5 and 6 h and for VCAM-1 at 1.5, 6, and 24 h (P < 0.05). B, Cytokines in the heart/aorta. The control and diabetic groups were significantly different for TNF-{alpha} and IL-1ß at 1.5 and 6 h (P < 0.05). C, Chemokines in the heart/aorta. The control and diabetic groups for MIP-2 and MIP-1{alpha} were significantly different at 1.5 and 6 h (P < 0.05).

 
The impact of a sc inoculation of LPS on the mRNA levels of TNF-{alpha} and IL-1ß was assessed in the heart/aortas of diabetic and normoglycemic mice (Fig. 3BGo). Within 90 min of sc LPS administration in the diabetic group there was an 8-fold increase in TNF-{alpha} and a 5-fold induction in IL-1ß. In comparison, these cytokines were induced only 2- to 3-fold in the nondiabetic mice. At 6 h in the diabetic mice, TNF-{alpha} and IL-1ß increased 23- and 18-fold, respectively. In the normal mice, the increases were 8- and 7-fold, respectively. For both time points, the differences were significant (P < 0.05).

MIP-2 and MIP-1{alpha} are chemotactic cytokines that are associated with atherosclerotic lesions. In diabetic animals, MIP-1{alpha} and MIP-2 mRNA levels increased 10- to 20-fold 90 min after inoculation. In contrast, there was 2- to 10-fold increase in normoglycemic mice (Fig. 3CGo). At 6 h, the fold induction in the heart/aorta of the diabetics was still higher than that of the normoglycemic mice. At both time points, the differences were significant (P < 0.05).

The degree to which sc injection of LPS at a distant site stimulated a response in the heart/aorta was surprising, particularly in the diabetic animals. For comparison, expression of these proinflammatory molecules was also measured at the site of inoculation. In Fig. 4Go, representative RNase protection assays (RPAs) are shown for VCAM-1, TNF-{alpha}, and MIP-2. At 90 min, the expression of each was significantly higher in the diabetic compared with the normoglycemic mice, whereas at 6 and 24 h, they were similar. Thus, the difference between the diabetic and normal group was more prolonged in the heart than at the site of inoculation.



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  		FIG. 4. Diabetes enhances the expression of VCAM-1, TNF-{alpha}, and MIP-2 at the site of inoculation. Subcutaneous LPS (200 µg) was injected into the scalp of diabetic (db/db) ({blacksquare}) and normoglycemic ({cjs2108}) mice. Expression of each molecule was assessed at the RNA level by RPA. The resulting autoradiograms and densitometric values normalized by GAPDH levels in the same lane are shown for diabetic (D) and control (C) mice. Each value represents the mean of three separate RPAs ± SEM and is expressed as the percent maximum expression. The control and diabetic groups were significantly different for the expression of all three genes at 1.5 h (P < 0.05).

 
In Table 1Go, the fold stimulation representing the difference between the highest level obtained and the zero time point in the heart/aorta is contrasted with that at the site of inoculation. The maximum value was obtained in every case in the diabetic group (data now shown). Surprisingly, the fold stimulation was higher in the heart/aorta than it was at the site of inoculation for all proinflammatory molecules except IL-1. This points to the sensitivity of the heart/aorta to endotoxemia, particularly in diabetic animals.


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  		TABLE 1. Fold maximum stimulation

 
TNF-{alpha} levels were measured in plasma obtained by cardiac puncture (Table 2Go). Plasma TNF-{alpha} levels peaked in the diabetic animals after 90 min after sc LPS inoculation and rose more slowly in the normoglycemic mice. As was noted for inflammatory mediator expression in the heart and aorta, the level of plasma TNF-{alpha} was significantly higher in the diabetic group, establishing a much greater systemic response to endotoxemia. In comparison, there was no difference in plasma endotoxin levels in the diabetic and control groups.


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  		TABLE 2. Circulating TNF-{alpha} and endotoxin levels

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Although it has been recognized for several years that coronary artery disease results from a complex inflammatory process in the vessel walls, the potential contribution of infection to this process has only recently been widely recognized. In fact, C-reactive protein, which is produced in the liver and is a reliable marker of systemic inflammation, is viewed as a better indicator of risk of cardiovascular disease than high levels of low-density lipoprotein (19). We report here that the inflammatory response in heart/aorta tissues of mice with type II diabetes to a mock infection accomplished by sc inoculation of LPS is considerably more rapid and more pronounced than that of normoglycemic littermates. These changes involved the expression of molecules that are thought to both initiate and promote atherosclerotic plaque formation and destabilization (10). Surprisingly, the degree to which the heart/aorta responded was even greater than that observed at the site of inoculation.

The mechanisms responsible for the enhanced inflammatory response in diabetic animals has not been conclusively established. It has been proposed that type II diabetes is associated with higher levels of TNF, in part because TNF is a product of adipose tissue, of which there is more in both humans and animal models of type II diabetes (20, 21). Thus, with enhanced production of TNF, cytokine networks become dysregulated and inflammatory responses are potentiated (22). Another contributing factor may be the production of advanced glycation end products that are present at higher levels in diabetic individuals. Advanced glycation end products have been reported to enhance oxidative stress and amplify inflammatory events in cardiovascular and other tissue (23, 24).

It is striking that bacterial infections linked to increased atherosclerosis tend to be chronic and Gram-negative and give rise to endotoxemia. The link between endotoxemia and atherosclerosis is supported by findings that individuals with high plasma endotoxin levels have a 3-fold higher risk of developing atherosclerosis (25). This is in agreement with results from a murine model in which endotoxemia enhanced formation and increased complexity of early atherosclerotic lesions (26). Thus, the presence of a chronic Gram-negative infection can cause endotoxemia and potentially accelerate the atherosclerotic process. Endotoxemia is known to be an important factor in chronic infection associated with increased risk of atherosclerosis (27, 28). The experimental endotoxemia produced in this study follows the pattern and time course observed in human endotoxemia resulting from remote bacterial infection (29, 30, 31). Thus, infections by Gram-negative organisms that can lead to endotoxemia have the capacity to up-regulate an outburst of cytokines, chemokines, and vascular adhesion molecules capable of initiating and promoting atherosclerosis (13). In addition to stimulation by circulating endotoxin, the heart and aorta are subjected to systemic inflammatory products induced by endotoxemia, such as TNF-{alpha} or other circulating proinflammatory cytokines that were not measured.

To the best of our knowledge, findings reported here are the first to demonstrate the dramatic effect that diabetes has on the inflammatory response of cardiovascular tissue to an infection or mock infection at a distant site.


   Acknowledgments
 
We thank Dr. Victoria Herrera for several helpful discussions and Weicheng Wu for technical assistance.


   Footnotes
 
This work was supported by grants from the National Institute of Dental and Craniofacial Research, DE11254 (D.T.G.), H2076801 and DE15989 (S.A.), and DE13191 (D.T.G. and S.A.).

Abbreviations: GAPDH, Glyceraldehyde-3-phosphate dehydrogenase; LAL, Limulus amebocyte lysate; LPS, lipopolysaccharide; MIP, macrophage inflammatory protein; RPA, RNase protection assay; VCAM, vascular cell adhesion molecule.

Received June 10, 2004.

Accepted for publication July 20, 2004.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
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