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ENDOCRINE AND DIABETES
Protects against Diabetes-Induced Impairment in Arachidonic Acid Dilation of Small Coronary Arteries
Departments of Internal Medicine, Mayo Clinic, Rochester, Minnesota (W.Z., X.-L.W., H.L.); and University of Iowa and VA Medical Center, Iowa City, Iowa (K.G.L.)
Received April 21, 2006; accepted July 20, 2006.
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Abstract |
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-induced reactive oxygen species (ROS) underlie the vascular dysfunction in diabetes, we examined the effects of (S)-13[(dimethylamino)-methyl]-10,11-14,15-tetrahydro-4,9:16,21-dimetheno-1H,13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadi-azacyclohexadecene-1,3(2H)-dione (LY333531; LY), a specific PKC inhibitor, on arachidonic acid (AA)-mediated dilation in small coronary arteries from streptozotocin-induced diabetic rats. This study was designed to determine whether diabetes impairs AA-induced vasodilation of small coronary arteries and whether this defect could be blunted by dietary treatment with LY. Coronary diameter was measured using videomicroscopy in isolated pressurized vessels. In controls, AA dose dependently dilated coronary arteries, with 1 µM producing 54.7 ± 3.1% and 30 µM producing 72.0 ± 3.0% dilation (n = 9). In diabetic rats, 1 µM AA only produced 31.4 ± 3.8% (n = 8; p < 0.01 versus control) and 30 µM 43.8 ± 3.7% dilation (n = 8; p < 0.001 versus control). Nitroprusside-mediated vasodilations were similar in control and diabetic rats. In contrast, in diabetic rats receiving LY, AA-mediated coronary dilations were normal. In controls, AA-mediated vasodilation was inhibited by miconazole (an inhibitor of cytochrome P450 epoxygenase) and by iberiotoxin (IBTX, an inhibitor of the large conductance Ca2+-activated K+ channel), but miconazole and IBTX had no effects in diabetic vessels. In diabetic rats receiving LY, the effects of miconazole and IBTX were similar to control. Superoxide dismutase restored responses to AA in diabetic vessels but had no effect in vessels from control or diabetic rats on LY. These results suggest that AA-mediated vasodilation in rat coronary arteries are impaired in diabetic rats due to increases in generation of ROS. LY protects against these defects in diabetes through inhibition of PKC-mediated production of ROS.
), and patients with diabetes have a 2- to 4-fold increase in the risk of coronary artery disease (Beckman et al., 2002a). Metabolic, humoral, and hemodynamic factors all contribute to the development of vascular dysfunction (Cooper et al., 2001). Endothelial dysfunction with impaired activity of various endothelial-derived factors plays an integral role in diabetic vasculopathy (De Vriese et al., 2000; Brownlee, 2001). The process by which hyperglycemia produces endothelial and vascular dysfunction is complex, but several major mechanisms have been proposed (Nishikawa et al., 2000; Brownlee, 2001; Cooper et al., 2001; Gutterman, 2002), including overactivity of the polyol pathway, accumulation of advanced glycation end products, and activation of protein kinase C (PKC). Each of these would result in an enhanced generation of ROS. Activated PKC mechanisms have received increasing attention (Way et al., 2001). Hyperglycemia stimulates PKC through the action of diacylglycerol and nonesterified fatty acids (Cooper et al., 2001; Egan et al., 2001). In particular, the isoform is increased in diabetic vascular tissues (Inoguchi et al., 1992), and administration of LY333531 (LY), a highly specific inhibitor of PKC, attenuates the various vascular abnormalities in streptozotocin-induced diabetic rats (Inoguchi et al., 1992; Ishii et al., 1996). Recently, oral administration of LY in humans has been shown to prevent impaired endothelium-dependent vasodilation caused by hyperglycemia (Beckman et al., 2002b). These findings position PKC as a key participant in the development of vascular dysfunction in diabetes mellitus.
Arachidonic acid (AA) is an important precursor for many vasoactive metabolites that are crucial for the regulation of vascular function. AA is metabolized by cyclooxygenase into prostaglandins and thromboxane; by lipoxygenase (LOX) into leukotrienes, lipoxins, and intrachain hydroxyeicosatetraenoic acids (HETEs); and by cytochrome P450 (P450) epoxygenase into epoxyeicosatrienoic acids and chain terminal HETEs (Foegh and Pamwell, 2002). AA produces potent dilation in human coronary arterioles that is dependent on the P450 pathway (Miura and Gutterman, 1998), whereas the dilation produced in rat mesenteric microvessels is mediated mainly through the LOX pathway (Miller et al., 2003; Zhou et al., 2005). However, the role of AA in the vascular dysfunction of diabetes mellitus is not fully known.
Enhanced PKC activities could produce vascular dysfunction through different mechanisms but the common denominator seems to be increase in ROS (Gutterman, 2002). PKC could induce ROS production through activation of NAD(P)H in vascular endothelial cells (Inoguchi et al., 2003). In addition, nitric-oxide synthase in diabetic vessels may become uncoupled, resulting in the generation of superoxide rather than NO (Hink et al., 2001). Increased ROS is known to affect the cyclooxygenase (Zou et al., 2002), LOX (Zhou et al., 2005), and P450 (Lin et al., 2005) enzymes, and it could significantly modulate AA metabolism and the vascular effects of its bioactive products. The goal of this study is to determine whether the AA-mediated dilation of small coronary arteries is impaired in streptozotocin-induced diabetic rats, and to determine the role of PKC in such impairment.
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Materials and Methods |
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; Ishii et al., 1996). LY is a highly specific inhibitor of PKC, and the LY-containing chow was specially prepared by Eli Lilly & Co. (Indianapolis, IN). Handling and care of animals, and all animal procedures were approved by the Institutional Animal Care and Use Committee, Mayo Foundation (Rochester, MN).
Vasoreactivity Measurements. Two to 4 weeks following induction of diabetes and administration of LY, rats were anesthetized with sodium pentobarbital (50 mg/kg i.p.). Hearts were rapidly excised and placed in ice-cold Krebs' solution that contained 118.3 mM NaCl, 4.7 mM KCl, 2.5 mM CaCl2, 1.2 mM MgSO4, 1.2 mM KH2PO4, 25 mM NaHCO3, and 11.1 mM dextrose. The secondary and tertiary branches (50-200 µm in intraluminal diameter) of the right and left coronary arteries from the epicardial surface as well as branches of the septal coronary arteries were carefully dissected and isolated free of surrounding myocardium and connective tissue under a dissecting microscope (Olympus SZ4045 stereo microscope, Olympus America Inc., Melville, NY). Isolated small coronary arteries (1-2 mm in length) were transferred to a custom-made vessel chamber filled with Krebs' solution. The arteries were mounted and secured between two borosilicate glass micropipettes (30-µm-diameter tips) with 10-0 ophthalmic suture. The lumen of the vessel was filled with Krebs' solution through the micropipettes and maintained at a constant pressure (no flow) of 60 mm Hg. The vessel chamber was transferred to an inverted light microscope stage (Olympus CK40) coupled to a video measurement system (VIA-100; Boeckeler Instruments, Inc., AZ) equipped with a videocamera, monitor, and calibrated video calipers for visualization and recording the intraluminal diameter as described previously (Zhou et al., 2005). Vessels were equilibrated for at least 30 min in oxygenated (20% O2, 5% CO2, balanced with N2, 37°C) Krebs' solution, which was continuously circulated through the vessel bath. Responses to cumulative additions of each compound were determined at 5-min intervals. The average diameter of the vessels used was 137 ± 5 µm for controls, 137 ± 8 µm for control on LY diet, 122 ± 6 µm for diabetic rats, and 123 ± 5 µm for diabetic rats on LY diet (p = N.S. among groups). Vessels were unacceptable for experiments if they demonstrated leaks, failed to produce >30% constriction to 60 mM KCl or to graded doses of endothelin-1, or failed to produce an 80% dilation with nitroprusside (10-4 M).
To assess the role of endothelium in responses, endothelium was removed by passing an air bubble (1-ml volume) through the isolated vessels. Vessels were used only if they did not relax with acetylcholine (10-4 M; <10% relaxation) but had normal response to nitroprusside (10-4 M; >80% dilation of constriction by endothelin-1) and to KCl (60 mM; >30% constriction of baseline resting diameter).
Pharmacological Interventions. All compounds were added abluminally, and the cumulative concentration responses were determined at 3- to 5-min intervals between doses. Vessels were constricted to 30 to 60% of baseline diameter with endothelin-1 (doses used were 3.6 ± 0.3 to 6.6 ± 0.6 nM). Concentration-response curves to acetylcholine (ACh; 10-11-10-4 M, endothelium-dependent), sodium nitroprusside (10-11-10-4 M, endothelium-independent), and AA (1 x 10-10-3 x 10-5 M) were determined.
To determine the mechanisms responsible for mediating dilation to AA, small coronary arteries were preincubated for 30 min with 10-5 M miconazole to inhibit the P450 epoxygenase pathway, or with 10-7 M iberiotoxin (IBTX) to block the large conductance Ca2+-activated K+ (BK) channels, before dose-response experiments. To determine the effects of ROS in vascular dysfunction, vessels were treated with 150 U/ml superoxide dismutase (SOD) for 30 to 45 min before measuring vasodilator response to ACh and AA. To determine the effects of acute PKC inhibition in vascular dysfunction, vessels were treated with 30 nM LY333531 for 30 min before measuring vasodilation response to AA.
Fluorescent Microscopy of Oxidative Stress. The oxidative fluorescent dye dihydroethidium (DHE) was used to evaluate the production of superoxide in coronary arteries as described previously (Miller et al., 1998). DHE is a chemically reduced ethidium derivative that is permeable to viable cells. DHE exhibits blue fluorescence in cytoplasm but can be oxidized in cells, reacting with superoxide to form ethidium, which intercalates DNA to produce bright red fluorescence (Munzel et al., 2002). Unfixed frozen ring segments of rat coronary arteries from control, diabetic, and LY-treated diabetic animals were cut into 30-µm-thick sections and placed on a glass slide. DHE (2 µM) was topically applied to each tissue section and incubated in a light-protected humidified chamber at 37°C for 30 min. Slides were then coverslipped, and images were obtained with a confocal laser microscope (LSM 510, Zeiss, Germany) with a 63x water immersion lens. DHE was excited at 488 nm and fluorescence emission was detected with a 585- to 615-nm band-pass filter. In addition, autofluorescence intrinsic to the internal elastic lamina, which separates the endothelium from smooth muscles and is present in small arteries, was detected using a 505- to 550-nm band-pass filter (green fluorescence) (Wong and Langille, 1996; Burnham et al., 2002), and transmitted light micrographs of the same sections were also obtained. Laser settings were identical for acquisition of images, and vessels from control, diabetic, and diabetic rats on LY were processed in parallel. The light micrograph and fluorescent images for DHE signals and internal elastic lamina were digitally merged to demonstrate anatomical distribution of ROS. The DHE signals were further analyzed densitometrically using Scion Image software (Scion Corporation, Frederick, MD), and the results were expressed as relative densitometric units per unit area.
Materials. DHE was purchased from Invitrogen (Carlsbad, CA). LY333531 was a generous gift from Eli Lilly & Co. and was solubilized in dimethyl sulfoxide as a 20 mM stock solution. All other chemicals were obtained from Sigma-Aldrich (St. Louis, MO). AA, ACh, and nitroprusside were solubilized in deionized water and stored under nitrogen at -20°C. Iberiotoxin was freshly prepared in Krebs' solution at 10-7 M. Streptozotocin was freshly prepared in sterile water before injection into the animals.
Statistical Analysis. Data are presented as mean ± S.E.M. n represents the number of vessels used in each experiment. All concentration-response relationships were analyzed using one-way analysis of variance with repeated measures. Pairwise comparisons among the groups were performed using Tukey test with SigmaStat software (Systat Software, Inc., Point Richmond, CA). Statistical significance was defined as p < 0.05.
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Coronary Vasoreactivity. Coronary arteries from diabetic rats dilated to sodium nitroprusside similar to controls (Fig. 1A), suggesting intact vascular smooth muscle function. However, dilation to ACh was significantly reduced in diabetic coronary arteries, with 1 µM ACh producing only 44% the dilation of control (29.1 ± 1.7% dilation in diabetic, n = 6 versus 66.4 ± 1.5% in control, n = 8; p < 0.001). Decreased responses to ACh suggest endothelial dysfunction in diabetic rats (Fig. 1B). However, in diabetic rats that received LY, ACh-induced dilation was preserved, with 1 µM ACh producing 55.9 ± 4.6% dilation (n = 9; p < 0.001 versus diabetic group). Control animals on LY diet also had normal responses to nitroprusside and to ACh (Fig. 1). These results suggest that inhibition of PKC by LY was protective against the development of endothelial dysfunction in diabetic animals.
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To determine the effect of acute PKC inhibition, control and diabetic vessels were exposed to 30 nM LY333531 for 30 min before determination of AA-mediated vasodilation. Short-term inhibition of PKC had no protective effects against abnormal AA-mediated vasodilation in isolated diabetic vessels (Fig. 3, A and B). These results suggest that vascular dysfunction in diabetes is produced by events downstream of PKC signaling and are not mitigated by acute PKC inhibition.
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activities in diabetic vessels may underlie the derangements of AA metabolism by P450 epoxygenase, and LY prevents the development of such abnormalities.
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Role of BK Channels. Since BK channels are important targets of AA vasoactive metabolites, we examined the role of BK channels on the abnormal AA-mediated dilation in diabetic coronary arteries by preincubation with 10-7 M IBTX. In control coronary arteries, IBTX produced significant inhibition of AA-mediated dilation (Fig. 5A), suggesting that BK channels were important targets of the vasoactive metabolites of AA. In contrast, IBTX had no effect in diabetic coronary arteries (Fig. 5B), suggesting that BK channels do not play a significant role either due to the lack of channel-activating vasodilators or abnormal channel function. However, in diabetic rats on LY diet, sensitivity to IBTX was preserved (Fig. 5C), and the coronary arteries from these rats behaved similarly as in control rats. These results suggest that inhibition of PKC preserves the role of BK channels and protects against the impairment of AA-mediated vasodilation in diabetes.
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activity in diabetes has been shown to be associated with an increased generation of ROS (Cooper et al., 2001; Inoguchi et al., 2003), we examined the effects of SOD on ACh-mediated relaxation in diabetic coronaries. Treatment with SOD did not affect the vasodilation produced by ACh in vessels from control rats (Fig. 6A). However, in diabetic vessels that showed impairment to ACh-mediated vasodilation, SOD significantly improved the effects of ACh (Fig. 6A). SOD had no effects on vessels from diabetic rats on LY diet, similar to that observed in control vessels (Fig. 6B). These results suggest that ROS is involved in the impairment in ACh-mediated vasodilation, and treatment with SOD could effectively ameliorate such dysfunction.
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Likewise, treatment with SOD had no effect on AA-mediated vasodilation in coronary arteries from control rats (Fig. 7A). However, SOD normalized the impaired vasodilation observed in diabetic coronaries to AA (Fig. 7A). Similar to controls, vessels from diabetic rats on LY diet were not affected by treatment with SOD (Fig. 7B). These results suggest that the impairment of AA-mediated vasodilation in diabetic vessels could be caused by overproduction of ROS, and treatment with SOD was able to maintain normal vessel function. The results from Figs. 6 and 7 together indicate that vascular endothelial dysfunction in diabetic rats might be due to enhanced ROS generated by the increase in PKC activities.
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activation produces oxidative stress, which leads to endothelial dysfunction in diabetes. These results indicate that administration of LY protects against the development of endothelial dysfunction in diabetes through the suppression of ROS generation by inhibition of PKC.
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Discussion |
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activity in diabetic vessels is a central mechanism that promotes endothelial dysfunction. Generation of superoxide from enhanced PKC activity seems to be the final common course that produces impairment in vasodilator responses in diabetic coronary arteries.
We found that AA is a potent vasodilator in small coronary arteries in rats, and this effect requires an intact endothelium. These results are in agreement with previous reports (Miura and Gutterman, 1998; Lu et al., 2005). In human coronary arterioles, the AA-mediated dilation was dependent on P450 and BK channel activities (Miura and Gutterman, 1998). AA metabolism in coronary arteries is ostensibly different from that in mesenteric arteries in which the LOX pathway produces 12-HETE as the predominant AA-derived vasodilator (Miller et al., 2003; Zhou et al., 2005). However, with the development of diabetes mellitus, AA lost its ability to produce endothelial-mediated relaxation in the rat small coronary arteries, similar to the mesenteric arteries in ZDF rats (Zhou et al., 2005). In normal rat coronary arteries, AA-mediated vasodilation is dependent on the products of P450 epoxygenase and on BK channel activation. However, these mechanisms of AA-mediated vasodilation are no longer effective in diabetic coronary arteries (Figs. 4 and 5). In contrast, in diabetic rats on LY diet, function of the P450 epoxygenase pathway and BK channels remain intact. It is important to point out that diabetic rats on LY diet are hyperglycemic, similar to diabetic rats on normal diet. These results suggest that the pathophysiological consequences of PKC elevation are central to the development of diabetic endothelial dysfunction, because inhibition of PKC by LY is able to maintain normal vascular function. However, acute inhibition of PKC did not restore normal vessel function (Fig. 3), suggesting that the events downstream of PKC are important in causing vascular dysfunction in diabetes mellitus.
Endothelial dysfunction in streptozotocin-induced diabetic rats was very extensive, involving multiple sites and multiple pathways. The major culprit seems to be generation of ROS associated with diabetes. Indeed, acute treatment with SOD was effective in reversing the endothelial defects and restoring normal function. We found that acute exposure to SOD restored the diabetic coronary artery's ability to respond to ACh and AA (Figs. 6 and 7). These findings suggest that the pathophysiological mechanisms are dynamic, modulating the target proteins in a time course of minutes, suggesting a post-translational modification of existing proteins and enzymes, rather than involving changes in gene expressions. These results are consistent with findings from other laboratories (Erdos et al., 2004). The exogenous SOD seemed to exert its effects extracellularly. Recently, it has been reported that extracellular SOD (ecSOD) is a major form of SOD in the vessel wall, playing a critical role in protecting the bioavailability of NO, and reduced ecSOD is associated with abnormal vascular reactivity in cardiovascular diseases, including arteriosclerosis (Fukai et al., 2002) and diabetes (Ciechanowski et al., 2005). Indeed, ecSOD polymorphism is associated with insulin resistance and susceptibility to type 2 diabetes (Tamai et al., 2006), and gene transfer of ecSOD improves endothelial function in rats with heart failure (Iida et al., 2005). We believe one of the major mechanisms through which ecSOD restores vascular function is by extracellular scavenging of ROS, so that the availability of NO and other vasodilators is preserved.
Enhanced generation of ROS in diabetes is well established, but its cause is less well defined. Recent evidence suggests that elevated levels of PKC might be an important contributor to this process. Activation of PKC is known to cause endothelial dysfunction (Tesfamariam et al., 1991). Hyperglycemia increases diacylglycerol, a potent activator of PKC, with PKC being preferentially elevated in the aorta and heart of diabetic rats (Inoguchi et al., 1992). In this study, the dietary administration of LY to diabetic rats had no effect on hyperglycemia, but it significantly prevented the development of endothelial dysfunction. In diabetic rats on LY diet, vasodilation to ACh and AA was either normal or close to normal with significant improvement compared with their counterparts on normal diet. These results suggest that enhanced PKC might underlie the development of diabetic vasculopathy. Enhanced PKC activity is known to inhibit BK channel (Shipston and Armstrong, 1996) and vascular ATP-sensitive K+ channel function (Hayabuchi et al., 2001; Chrissobolis and Sobey, 2002), but the sequelae of elevated PKC in diabetes seems to have a much wider impact than its kinase effects. Indeed, PKC has been shown to enhance production of ROS in diabetes through activation of superoxide-producing enzymes, including NADPH oxidase (Inoguchi et al., 2003). In addition, diabetic rats are found to have a PKC-dependent up-regulation of a dysfunctional, superoxide-producing, uncoupled endothelial nitric-oxide synthase (nitric-oxide synthase III) (Hink et al., 2001). The PKC-mediated production of superoxide may interact with NO, reducing NO availability, and produce the highly reactive peroxynitrite. Peroxynitrite has been shown to tyrosine nitrate important proteins, and enzymes such as prostaglandin I2 synthase, reducing its activity and resulting in diminished bioavailability of prostaglandin I2 (Zou et al., 2002). We have also reported that in ZDF rat mesenteric arteries, tyrosine nitration of LOX is enhanced, resulting in reduced LOX activity and 12-S-HETE production (Zhou et al., 2005). Cytochrome P450 enzymes are also known targets of peroxynitrite-mediated nitrotyrosine formation and inactivation of the enzyme (Lin et al., 2005). Hence, all three pathways of AA metabolism can be modulated by superoxide/peroxynitrite and may account for their functional impairment in diabetes. Recently, peroxynitrite has been shown to cause nitration and functional loss of voltage-gated K+ channels in rat coronary microvessels exposed to high glucose (Li et al., 2004). BK channels are also known to be inhibited by ROS, through direct effects of peroxynitrite (Liu et al., 2002) and oxidation of specific cysteine residues on the channel by hydrogen peroxide (Tang et al., 2004). These mechanisms may contribute to our observation that BK channel-mediated vasodilation is impaired in diabetic vessels (Fig. 5). Hence, the enhanced PKC activity promotes formation of ROS, inactivating key enzymes and proteins that produce vasodilators and inhibit target effector function.
Our results demonstrated that dietary administration of LY, a PKC inhibitor, could prevent the development of endothelial dysfunction and maintain AA-mediated vasodilation, suggesting this strategy could have important therapeutic implications in the treatment of diabetes. LY has been shown to have protective effects against vascular dysfunction (Ishii et al., 1996). LY prevented the impairment of endothelium-dependent vasodilation by hyperglycemia (Beckman et al., 2002b), attenuated leukocyte entrapment in retinal microcirculation (Nonaka et al., 2000), corrected the neurovascular dysfunction (Cameron and Cotter, 2002), normalized glomerular hyperfiltration, reduced albumin excretion, and improved renal function in diabetes (Tuttle and Anderson, 2003). In our experiments, LY did not improve blood glucose regulation but was able to restore endothelial function in diabetic rats and its effects are similar to treating vessels with SOD. With diabetic rats on LY, SOD has no further beneficial effects (Figs. 6 and 7), suggesting LY was efficacious in suppressing the production of ROS in diabetes. These results are supported by fluorescent microscopy using DHE (Fig. 8), showing that coronary arteries from diabetic rats had an elevated level of oxidative stress but not those from diabetic rats receiving LY. Our results support the notion that inhibition of PKC together with antioxidant therapy could be beneficial to vascular function in patients with diabetes. Indeed, it is important to note that ruboxistaruin (LY333531) mesylate is in the process of undergoing phase III clinical trials in patients with type 1 and type 2 diabetes mellitus to determine its efficacy in preventing the development of diabetic microvascular complications.
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Acknowledgements |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: PKC, protein kinase C; ROS, reactive oxygen species; LY333531 (LY), (S)-13[(dimethylamino)methyl]-10,11-14,15-tetrahydro-4,9:16,21-dimetheno-1H,13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-dione; AA, arachidonic acid; P450, cytochrome P450; LOX, lipoxygenase; HETE, hydroxyeicosatetraenoic acid; ACh, acetylcholine; IBTX, iberiotoxin; BK, channel, large conductance Ca2+-activated K+; SOD, superoxide dismutase; DHE, dihydroethidium; ecSOD, extracellular superoxide dismutase.
Address correspondence to: Dr. Hon-Chi Lee, Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN 55905. E-mail: lee.honchi{at}mayo.edu.
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