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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:918-923.)
© 1995 American Heart Association, Inc.

Articles

Inhibition of Atherosclerosis and Myocardial Lesions in the JCR:LA-cp Rat by ß,ß'-Tetramethylhexadecanedioic Acid (MEDICA 16)

James C. Russell; Roger M. Amy; Sandra E. Graham; Peter J. Dolphin; George O. Wood; Jacob Bar-Tana

From the Departments of Surgery (J.C.R., S.E.G.) and Pathology (G.O.W.), University of Alberta, Edmonton; British Columbia Cancer Agency (R.M.A.), Vancouver; Department of Biochemistry (P.J.D.), Dalhousie University, Halifax, Nova Scotia, Canada; and Department of Human Nutrition and Metabolism (J.B.-T.), Hadassah Medical School, Hebrew University, Jerusalem, Israel.

Correspondence to Dr J.C. Russell, Department of Surgery, 275 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.

	Abstract

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Abstract Atherosclerosis-prone, insulin-resistant JCR:LA-cp male rats were treated from 6 weeks to 39 weeks of age with ß,ß'-tetramethylhexadecanedioic acid (MEDICA 16). Body weights were reduced (13%, P<.001) at 36 weeks without any accompanying decrease in food consumption. The treatment did not cause any significant change in plasma glucose or fasting insulin concentrations. There was a significant decrease in the extreme hyperplasia of the islets of Langerhans (38%, P<.05). The marked VLDL hypertriglyceridemia was decreased by 70% (P<.001), with an accompanying significant reduction in cholesterol concentrations. The severity of raised atherosclerotic lesions on the aortic arch was very markedly reduced (P<.01) in treated rats. This was accompanied by a reduction (P<.01) in the incidence of ischemic myocardial lesions. We conclude that long-term (33 weeks) MEDICA 16 treatment of an animal model for the obesity/insulin-resistant/hyperlipidemic syndrome not only markedly improved lipid metabolism, but also inhibited the development of advanced cardiovascular disease.

Key Words: MEDICA 16 • myocardial lesions • hypertriglyceridemia • JCR:LA-cp rat • atherosclerosis

	Introduction

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The JCR:LA-cp rat is one of a number of strains incorporating the autosomal recessive cp gene originally isolated by Koletsky.^{1 2} The rats are, if homozygous normal (+/+) or heterozygous (+/cp), lean and indistinguishable from the parent LA/N strain. If homozygous cp (cp/cp), the rats are obese from an early age, insulin resistant, and hyperinsulinemic and exhibit a marked hyperlipidemia due to hepatic hypersecretion of VLDL.^{3 4 5} This strain is the only one incorporating the cp gene to exhibit spontaneous atherosclerosis and ischemic myocardial lesions.^{6 7 8 9} The atherosclerosis and myocardial lesions are essentially confined to the cp/cp male rats, with lean rats of both sexes and cp/cp females being spared.^{8 9} Although the fatty Zucker (fa) gene and the cp gene are allelic,^{10 11} they are clearly different in effect. In particular, the fa/fa (fatty) Zucker rat does not develop as severe a metabolic disturbance as does the JCR:LA-cp rat, nor does the former exhibit any frank cardiovascular disease.^{8 12}

ß,ß'-Tetramethylhexadecanedioic acid (MEDICA 16) is the most effective of a series of long-chain fatty acids developed as hypolipidemic and antiobesity/anti–insulin resistance agents.¹³ The hypolipidemic effect of MEDICA 16¹⁴ can be accounted for by the inhibition of long-chain fatty acid and cholesterol synthesis,^{15 16} together with the activation of triglyceride-rich plasma lipoprotein clearance mediated by a decrease in plasma apo C-III.^{17 18} The antiobesity effect may be accounted for by increased lipolysis complemented by liver calorigenesis due to the thyromimetic activity of the drug.^{19 20 21} The antidiabetogenic effect is accounted for by the adipose-reductive effect of the drug and by a concomitant decrease in insulin resistance.²²

Short-term (14 days) treatment of cp/cp rats of the JCR:LA-cp strain with MEDICA 16 resulted in a marked decrease (up to 80%) in plasma triglycerides.²³ This was shown to be due to a decreased rate of VLDL production by the liver, secondary to inhibition of fatty acid synthesis at the level of ATP citrate lyase. There was also evidence of an increased rate of VLDL catabolism. Despite the lack of improvement in insulin and glucose metabolism, the changes in lipid metabolism were sufficiently great to suggest that MEDICA 16 might be expected to protect against the development of vascular and myocardial damage in this animal model. We report here that long-term treatment with MEDICA 16 does offer such protection.

	Methods

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Animals
Male rats were bred in our established colony of JCR:LA-cp rats, both +/+ and cp/cp, as previously described.^{6 7} They were weaned at 3 weeks of age and maintained in polycarbonate cages on wood chip bedding and exposed to a 12/12-hour light/dark cycle. The room was maintained at 20°C and 55% relative humidity. Food, available at all times, was Wayne Rodent Blox (Harlan Sprague Dawley Inc), a grain-based diet containing less than 4% total fat.²⁴ The food was obtained in powdered form, and MEDICA 16, synthesized as previously described,¹⁵ was incorporated at 0.25% (wt/wt) for the treated rats. The food, both control and treated, was moistened with water, extruded into pellet form, and air dried. This diet was fed to the rats from 6 weeks of age. The rats were weighed on a regular basis and food consumption was recorded. Otherwise the animals were left undisturbed until 39 weeks of age.

The rats were starved overnight at 39 weeks of age and anesthetized with halothane in oxygen. Blood was sampled from the left ventricle of the heart, and the rat was then perfusion-fixed with 1.25% glutaraldehyde and 1.85% formaldehyde in Tyrode's solution at 100 mm Hg. After their removal, the heart, liver, duodenum, kidneys, spleen, adrenals, testes, lungs, and brain were further fixed in neutral buffered formalin, the pancreas was fixed in Bouin's solution and 70% ethanol, and the aortic arch was fixed in 2.5% glutaraldehyde. The tissues fixed in formalin and the pancreas were processed by conventional histological techniques, sectioned, and stained with hematoxylin and eosin. The hearts were cut transversely into three blocks: apex, midheart, and base. Adjacent sections were taken from each block of the heart and stained with hematoxylin and eosin as well as Masson's trichrome stain. The heart sections were examined by an experienced pathologist who was not aware of the group to which each rat belonged, and myocardial lesions were identified and their frequencies determined as described previously.⁹ Lesion stages were classified as follows: stage 1, areas of necrosis; stage 2, areas of cell lysis with chronic inflammatory cell infiltration; stage 3, nodules of chronic inflammatory cell infiltration; and stage 4, old scarred lesions. The pancreatic sections were examined histologically, and the cross-sectional areas of the islets of Langerhans and their volume densities were determined by use of an image analysis system (GENIAS25, Joyce-Loebl Div, Vickers Plc). Measurement was based on five random fields at x10 magnification from a section of the tail of the pancreas. The aortic arch was dissected free of all extraneous tissue and split along the greater and lesser curves. The two halves of the arch, including the stumps of the branches, were postfixed with osmium tetroxide and uranyl acetate, dried with graded ethanol solutions, and triple-point dried from propylene oxide. The mounted segments were sputter-coated with gold, and the intimal surfaces were examined completely by use of a Hitachi scanning electron microscope (model S2500). Lesions were identified and classified as areas of adherent fibrin, raised intimal lesions, areas of adherent macrophages, or areas of de-endothelialization. All lesions for each animal were recorded photographically, and each type was assigned a severity score. The scale used had a range of 0 to 3, with 0 representing the absence of any lesions and 3 representing the most severe involvement.

Plasma glucose was measured by use of a rapid glucose oxidase method (Beckman Instruments). Insulin was assayed by use of a double antibody radioimmunoassay technique (Kabi Pharmacia Diagnostics AB) with rat insulin standards. Serum lipid concentrations were determined by the gas chromatographic total lipid profile technique of Kuksis et al.²⁵ Statistical analysis was by ANOVA and Wilcoxon's rank sum test, as appropriate, with a value of P<.05 for the two-tailed test taken as significant.²⁶

All care and treatment of the rats were in conformity with the Guidelines of the Canadian Council on Animal Care and subject to prior institutional review and approval.

	Results

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Food consumption data for the cp/cp rats, both MEDICA 16 treated and control, were essentially identical, as shown in Fig 1. Lean control rats (+/+) ate significantly less throughout the experimental period. Body weights of the MEDICA 16–treated cp/cp rats were consistently lower than those of the control rats, although the former remained much greater than those of the +/+ control animals (Fig 1). The lower body weights of the treated rats became significant at 12 weeks of age (P<.05) and remained highly significant thereafter (P<.001). As shown in Table 1, there was no significant change in fasting plasma glucose, whereas insulin concentrations were highly variable, making the even quite substantial differences apparently induced by treatment nonsignificant. However, there was a significant (38%, P<.01) decrease in volume density of the islets of Langerhans. The pancreases of the MEDICA 16–treated rats showed abnormal islet structure and evidence of pancreatitis similar to those seen in the cp/cp control animals, although less severe, as illustrated in Fig 2. The pancreases of MEDICA 16–treated rats also contained frequent smaller, essentially normal islets, as shown in Fig 2D.

View larger version (26K): [in this window] [in a new window]   Figure 1. Food consumption (A) and body weight (B) of male rats. Values are mean±SD for 10 rats in each group. indicates +/+ control; , cp/cp control; , cp/cp ß,ß'-tetramethylhexadecanedioic acid–treated.

View this table: [in this window] [in a new window]   Table 1. Plasma Glucose, Insulin Concentrations, and Islet of Langerhans Volume Density in ß,ß'-Tetramethylhexadecanedioic Acid–Treated Male Rats

View larger version (157K): [in this window] [in a new window]   Figure 2. Photomicrographs of pancreatic sections from 9-month-old male JCR:LA-cp rats show normal islet of Langerhans from a +/+ control rat (A); highly hyperplastic islets from a cp/cp control rat (B); large islets and pancreatitis in a cp/cp ß,ß'-tetramethylhexadecanedioic acid–treated rat (C); and several small, essentially normal islets and one moderately enlarged islet from a treated rat (D). Sections were stained with hematoxylin and eosin. Bars indicate 200 µm.

Table 2 shows the serum lipid concentrations in the 39-week-old rats. The long-term MEDICA 16 treatment resulted in a 70% reduction in triglycerides and significant decreases in total cholesterol (approximately 30%) and phospholipids (38%).

View this table: [in this window] [in a new window]   Table 2. Serum Lipid Concentrations in ß,ß'-Tetramethylhexadecanedioic Acid–Treated Male Rats

Scanning electron photomicrographs of the aorta, illustrating typical raised lesions with severity scores of 0 to 3, are shown in Fig 3. A score of 0 represents a smooth endothelial surface throughout, and a score of 3 represents a large raised lesion with abnormal overlying endothelium and desquamation. The extent of adhesion of macrophages to the endothelium was similarly assessed, and examples of moderate involvement (score of 2) and extensive involvement (score of 3) are shown in Fig 4A and 4B, respectively. As shown in Table 3, MEDICA 16 treatment of the cp/cp rats resulted in a marked and very significant reduction in the severity of atherosclerotic raised lesions on the aortic arch (P<.01). The reduction seen in the incidence of adherent macrophages was also substantial and significant (P<.05). The extent of de-endothelialization was apparently reduced, but this was not statistically significant. As shown in Table 4, the frequency of old, mature myocardial lesions (stage 4) was also markedly and significantly reduced (P<.01) in the MEDICA 16–treated rats. Photomicrographs of representative lesions are shown in Fig 5, illustrating the decreased size of lesions in the MEDICA 16–treated rats.

View larger version (172K): [in this window] [in a new window]   Figure 3. Scanning electron photomicrographs showing raised intimal lesions on the aortic arches of 9-month-old JCR:LA-cp rats. A, +/+ control: score of 0, clean smooth endothelial surface. B, cp/cp: score of 1, abnormal endothelial cells overlying a small raised lesion. C, cp/cp: score of 2, a moderate raised lesion with highly abnormal overlying endothelial cells. D, cp/cp: score of 3, extensive raised lesion with adherent macrophages and limited desquamation of endothelium cells. Bars indicate 10 µm.

View larger version (146K): [in this window] [in a new window]   Figure 4. Scanning electron photomicrographs show adherent macrophages on the aortic arches of 9-month-old cp/cp male rats. A, score of 2, small focus of adherent macrophages over an area showing endothelial damage. B, score of 3, an area of a large field of macrophages on abnormal endothelium with occasional entrapped erythrocytes. In the absence of macrophages, the score is 0 (no example shown). Bars indicate 10 µm.

View this table: [in this window] [in a new window]   Table 3. Severity Scores of Aortic Arch Lesions in cp/cp Male Rats Treated With ß,ß'-Tetramethylhexadecanedioic Acid

View this table: [in this window] [in a new window]   Table 4. Frequency of Myocardial Lesions in cp/cp Male Rats Treated With ß,ß'-Tetramethylhexadecanedioic Acid

View larger version (146K): [in this window] [in a new window]   Figure 5. Photomicrographs show representative myocardial lesions from control and ß,ß'-tetramethylhexadecanedioic acid (MEDICA-16)–treated cp/cp male rats. A, typical stage 2 lesion from a control rat. B, very small, typical stage 2 lesion from a MEDICA 16–treated rat. Sections were stained with hematoxylin and eosin. Bars indicate 200 µm.

Detailed examination of the histological sections of the liver, duodenum, kidneys, spleen, adrenals, testes, lungs, and brain of the 39-week-old rats revealed no significant abnormalities in any of the animals.

	Discussion

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Long-term treatment of cp/cp male rats with MEDICA 16 resulted in a hypolipidemic effect similar to that we previously reported after short-term (2 weeks) treatment.²³ However, while short-term treatment with MEDICA 16 caused no significant change in body weight, the long-term–treated rats had significantly lower body weights despite unchanged food intake. The reduced rate of weight gain and lower body weight, together with the very marked reduction in serum VLDL concentration, must therefore reflect a significant redirection of diet-derived glucose from triglyceride synthesis. The reduced flow of triglyceride in VLDL should reduce adipocyte accumulation of lipid, and thus of body weight, as observed. Such changes must be balanced by increased glucose oxidation elsewhere, as food consumption was not significantly reduced. The highly variable fasting insulin levels that are characteristic of the cp/cp rat may have obscured a real increase in insulin sensitivity. The substantial decrease in islet volume density and the presence of small, essentially normal, islets in the MEDICA 16–treated rats suggest that real changes in the insulin metabolism occurred. An expected component of this would be reduced insulin secretion, particularly postprandially, but the present results cannot address this or the metabolic fate of the redirected glucose. These changes in metabolic status occurred without any concomitant toxic effects resulting in histologically detectable abnormalities. At very high doses (650 mg · kg^-1 · d^-1), MEDICA 16 has been found to induce hepatic peroxisomal proliferation²⁷ ; however, this effect is species specific and does not occur in humans. No other toxic effects have been found in rodents.

MEDICA 16 is one of the most powerful hypotriglyceridemic agents in the cp/cp rat that we have found, causing a 77% decrease in triglycerides at 12 weeks of age²³ and a 71% decrease at 39 weeks of age. The only agent we have studied that is more effective is fluvastatin, which caused a 90% reduction in triglyceride levels in the cp/cp rat and resultant levels near those of the +/+ control rats (J.C.R., PhD, unpublished data). We have previously shown that the very marked hypolipidemic effects of MEDICA 16 are due primarily to the inhibition of fatty acid synthesis of the ATP citrate lyase step and resultant decrease in hepatic VLDL secretion.²³

The overall hypolipidemic, weight-reductive, and antidiabetic effects were reflected by a major decrease in atherosclerosis in MEDICA 16–treated rats. Thus, raised intimal lesions, adherent macrophages, and desquamation of the endothelium were all very significantly reduced. In particular, the lower incidence of areas of adherent macrophages suggests a reduced level of intimal pathophysiological processes in general and of atherogenesis. The improvement in the state of the aortic arch in the MEDICA 16–treated rats is complemented by the lower incidence of stage 4 myocardial lesions. These mature lesions represent a permanent record of the largest of the ischemic lesions cumulated over the life of the rat.⁹ Smaller stage 2 lesions, upon fibrosis and contraction, become invisible. In confirmation of this, stage 2 lesions found in the hearts of the MEDICA 16–treated rats were all very small. We have previously reported a similar effect in cp/cp male rats treated with nifedipine.²⁸ In that case, the smaller stage 2 lesions and the reduction in the frequency of stage 4 lesions were suggested to be due to the inhibition of arterial vasospasm secondary to vascular lesions. In the case of MEDICA 16 treatment, we have clear evidence of a reduction in the atherosclerotic damage to the artery. This reduction in myocardial damage should be ascribed to the overall effect exerted by MEDICA 16.

The hypolipidemic effect per se is very dramatic and probably plays an important role, although treatment modes that lower the very high plasma lipid levels of cp/cp rats by 50% do not reduce myocardial lesion frequency.^{24 29} The results are consistent with our working hypothesis that the insulin-resistant state, through hyperinsulinemia, transient hyperglycemia, or both, is the initiator of the intimal damage. The damage to endothelial cells leads, in the presence of hyperlipidemia, to the development of raised intimal (atherosclerotic) lesions and functional impairment of the vessel wall, with susceptibility to vasospasm.^{28 30} MEDICA 16 appears to have sufficient protective effects against both abnormalities leading to atherogenesis to markedly inhibit vascular lesion development. The cp/cp rat is, in our view, the best available animal model of the metabolic syndrome, showing all the critical elements, including atherosclerotic cardiovascular disease. The evidence to date is consistent with the possibility that the syndrome in the cp/cp rat, including the core abnormality of insulin resistance, may originate in abnormal lipid metabolism. The overall beneficial metabolic effects of MEDICA 16 indicate that it affects a central mechanism that links the various parameters of the metabolic syndrome. Although treatment with MEDICA 16 did not completely prevent the development of atherosclerotic lesions in the cp/cp rats, the improvement in the status of the aorta was very substantial. Moreover, it was sufficient to cause a major reduction in end-stage disease, ie, ischemic myocardial lesions. This suggests that MEDICA 16 may well offer protective effects against myocardial disease in humans.

	Acknowledgments

 
This work was supported in part by the Heart and Stroke Foundations of Alberta and New Brunswick. We are indebted to Bruce Stewart, Ming Chen, and Angela Fazikas for invaluable technical assistance.

Received December 17, 1994; accepted April 4, 1995.

	References

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				J. C. Russell, D. Ravel, J.-P. Pégorier, P. Delrat, R. Jochemsen, S. F. O'Brien, S. E. Kelly, S. T. Davidge, and D. N. Brindley Beneficial Insulin-Sensitizing and Vascular Effects of S15261 in the Insulin-Resistant JCR:LA-cp Rat J. Pharmacol. Exp. Ther., November 1, 2000; 295(2): 753 - 760. [Abstract] [Full Text]

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