Published online before print October 25, 2007, doi: 10.1161/ATVBAHA.107.154294
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© 2008 American Heart Association, Inc.
Integrative Physiology/Experimental Medicine |
The Mechanistic Basis for the Disparate Effects of Angiotensin II on Coronary Collateral Growth
From the Department of Integrative Medical Sciences (C.K., P.R.), Northeastern Ohio Universities College of Medicine, Rootstown; and the Departments of Physiology (B.P.) and Pharmacology (R.R.), Louisiana State University Health Sciences Center, New Orleans.
Correspondence to Petra Rocic, PhD, Department of Integrative Medical Sciences, Northeastern Ohio Universities College of Medicine, 4209 State Route 44, PO Box 95, Rootstown, OH 44275. E-mail procic{at}neoucom.edu
Abstract
Objective— We hypothesize that controversial effects of angiotensin II (Ang II) are attributable to its regulation of reactive oxygen species (ROS) and ROS-dependent signaling.
Methods and Results— Coronary collateral growth (CCG) was stimulated in normal (WKY) and syndrome X (JCR) rats by transient/repetitive ischemia (RI). Blood flow was measured in the normal (NZ) and the collateral-dependent (CZ) zone. In WKY, RI increased CZ flow (0.84 mL/min/g), but RI+subpressor Ang II increased it more (1.24 mL/min/g). This was associated with transient p38 and sustained Akt activation. A hypertensive dose of Ang II decreased CZ flow (0.69 mL/min/g), which was associated with sustained p38 and transient Akt activation. AT1R blockade by candesartan abrogated CZ flow in WKY (0.58 mL/min/g), reduced myocardial superoxide, and blocked p38 and Akt activation. RI-induced CZ flow in JCR was significantly decreased compared with WKY (0.12 mL/min/g), associated with a large increase in superoxide and lack of p38 and Akt activation. CZ flow in JCR was partially restored by candesartan (0.45 mL/min/g), accompanied by reduction in superoxide and partial restoration of p38 and Akt activation.
Conclusion— Ang II/AT1R blockade, at least in part, regulates CCG via generating optimal ROS amounts and activating redox-sensitive signaling.
Ang II regulates repetitive ischemia (RI)-induced coronary collateral growth (CCG) via ROS generation and redox-sensitive signaling. In normal oxidative stress, AT1R blockade decreases CCG; in elevated oxidative stress (metabolic syndrome), AT1R blockade rescues CCG by normalizing oxidative stress and activating p38 and Akt.
Key Words: Angiotensin II • syndrome X • coronary disease • signal transduction
A well-developed coronary collateral circulation reduces infarct size and incidence of sudden death.1 Despite the importance of collaterals, there has been minimal success in stimulating their growth in patients with coronary artery disease.2,3 Whereas the roles of many growth factors, including the vascular endothelial growth factor (VEGF) and basic fibroblast growth factor, in angiogenesis and collateral growth are well accepted, the role of Angiotensin II (Ang II) is newly emerging and controversial. Ang II has been reported to both inhibit and promote angiogenesis and collateral growth. Angiotensin converting enzyme inhibitors inhibited angiogenesis in tumors.4 Angiotensin type 1 receptor (AT1R) blockers inhibited collateral growth in a model of hind limb ischemia.5 In contrast, treatment with ACE inhibitors and AT1R blockers increased tumor angiogenesis.5 One study investigated the effect of long term ACE and AT1R inhibition on myocardial angiogenesis.6 The effect of Ang II on repetitive ischemia (RI)-induced coronary collateral growth (CCG) has not been investigated. Although angiogenesis and collateral growth are distinct processes, we hypothesized that some of the same cellular mechanisms regulated by Ang II–mediated reactive oxygen species (ROS) production and ROS-sensitive signaling, involved in angiogenesis, might control collateral growth, and thus that we might observe similar disparate effects of Ang II on RI-induced CCG.
See page 4
Elevated oxidative stress is a hallmark of vascular disease. We have recently shown that very high or very low amounts of myocardial superoxide inhibited CCG.7 Furthermore, we have shown that, analogous with the failure of clinical trials using VEGF,2,3 treatment with VEGF alone did not improve CCG in an animal model of elevated oxidative stress, endothelial dysfunction, and vascular disease, the Zucker obese prediabetic rat (ZOF).8 However, additional treatment with ecSOD partially rescued collateral growth in these animals.8 Superoxide and hydrogen peroxide production in cultured myocytes, vascular smooth muscle, fibroblasts, and endothelial cells in response to Ang II has been thoroughly documented. We hypothesized that the disparate effects of Ang II may be attributable to its regulation of myocardial oxidative stress, so that treatment with Ang II on the background of the normal oxidative state is beneficial but treatment on the background of elevated basal oxidative stress is detrimental to CCG. Thus, we investigate the effect of AT1R blockade on CCG in a rat model of the metabolic syndrome (Syndrome X), the JCR rat, and the effect of treatment with subpressor and hypertensive Ang II in healthy Wistar-Kyoto (WKY) rats.
We have recently shown that transient activation of the redox-sensitive p38 MAP kinase (p38) was required for CCG.7 Ang II is known to activate p38,9,10 as well as redox-sensitive Akt.9 Both are involved in cell survival,11,12 proliferation,13 and migration,14,15 processes necessary for CCG. We hypothesized that in addition to regulation of myocardial oxidative stress, differential activation of these signaling intermediates by Ang II in healthy animals (WKY) versus animal models of vascular disease (JCR, hypertensive WKY) may provide a mechanistic basis for the controversial effects of Ang II.
Here, we demonstrate that AT1R blockade on the background of the normal myocardial oxidative state (WKY) is detrimental to CCG. In contrast, AT1R blockade on the background of elevated oxidative stress (JCR) partially rescues CCG. In WKY, treatment with a subpressor (nonhypertensive) dose of Ang II further augments CCG, whereas treatment with a hypertensive dose abrogates CCG. Furthermore, we demonstrate that the amount of myocardial oxidative stress and extent and duration of p38 and Akt activation provide a part of the underlying molecular mechanisms for these disparate effects of Ang II and AT1R blockade.
Materials and Methods
Rat Model of Coronary Collateral Growth
Three- to 4-month-old male WKY or JCR rats were used for implantation of an occluder over the left anterior descending coronary artery (LAD). The RI protocol is: 8 40-sec occlusions, every 20 minutes for 2 hours and 20 minutes followed by a period of "rest" for 5 hours and 40 minutes, 3 per day for 10 days. The JCR rat (Charles Rivers, Wilmington, MA) is a cross between the Zucker obese diabetic rat and the spontaneously hypertensive rat and is hypertensive, obese, hyperglycemic, hyperlipidemic, and insulin resistant, thus mimicking Syndrome X.7,8,16
Microsphere Measurements of Myocardial Blood Flow
Microspheres (5x105) labeled with 57Co (at initial surgery) or 103Ru (at day 10 of RI) were injected into the left ventricle (LV). An arterial blood reference sample was withdrawn. Collateral-dependent zone was identified using fluorescent microspheres. Blood Flow=[(radioactive count in myocardial tissue)x(blood withdrawal rate)/(radioactive count in blood)]/(myocardial tissue weight). All experiments were n=8. Data were analyzed by 2-way ANOVA followed by t test. P<0.05 determines statistical significance.8,16
Measurement of O2·–
O2·– production was evaluated using dihydroethidium (DHE) and electroparamagnetic resonance (EPR). DHE was injected into the LV (60 µg/kg) on days 1 to 3 of RI for 20 minutes before 2 consecutive occlusions. Hearts were removed and frozen. DHE fluorescence was detected on 5-µm cryo-microtome sections (excitation/emission at 518/605 nm). Images were analyzed by Metamorph Software on n=3 (5 sections per heart). A Bruker EMX spectrometer was used for X-Band EPR measurements using 1-hydroxy-3-carboxy-pyrrolidine (CP-H). Animals underwent 2 consecutive occlusions, hearts were removed, collateral-dependent and normal zones separated, and CP-H (238 µg/100 mg tissue) added to samples immediately. Tissue was homogenized by sonication, and frozen in liquid nitrogen (LN2). O2·– concentration was calculated from arbitrary units (AU) (3.4x106 AU/nM). P<0.05 determined statistical significance.7
Western Blot Analysis
Collateral-dependent and normal zones were separated, and snap-frozen. Proteins were extracted as previously described.7 Phospho-specific and total anti-p38 and anti-Akt antibodies (Cell Signaling) were used for Western blotting. Bands were quantified using NIH Image. All experiments are n=3, analyzed by 2-way ANOVA followed by t test. All data were normalized to protein expression, which did not change in any treatment group. P<0.05 determined statistical significance.
Results
RI-Induced CCG Is Compromised in JCR Rats
Collateral flow in WKY animals increased from 0.13±0.02 mL/min/g on day 0 to 0.84±0.02 mL/min/g on day 10 of RI (collateral-dependent/normal zone flow ratio at day 10 of RI was 0.84, ie, blood flow in collateral-dependent zone was 84% of flow in the normal zone Figure 1), demonstrating significant collateral development in the collateral-dependent zone. In contrast, collateral-dependent flow in the JCR rats did not significantly increase after 10 days of RI (0.09±0.01 mL/min/g on day 0 to 0.12±0.05 mL/min/g on day 10 of RI [collateral-dependent/normal zone flow ratio at day 10 of RI was 0.12] Figure 1), indicating that JCR rats fail to develop collaterals in response to RI.
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AT1R Blockade Partially Restores CCG in JCR, but Abrogates CCG in WKY Rats Independently of Effects on Blood Pressure
Candesartan was given to JCR and WKY animals for 21 days (3 mg/100 mL in drinking water), resulting in significant reduction in blood pressure (105±12 mm Hg for WKY+RI versus 85±7 mm Hg for WKY+RI+candesartan; 156±11 mm Hg for JCR+RI versus 131±6 for JCR+RI+candesartan). Candesartan increased collateral flow in JCR animals from 0.08±0.04 mL/min/g on day 0 to 0.45±0.04 mL/min/g on day 10 of RI (collateral-dependent/normal zone flow ratio at day 10 of RI was 0.45; Figure 1). In contrast, candesartan abrogated CCG in the WKY rat (0.11±0.02 mL/min/g on day 0 to 0.58±0.04 mL/min/g on day 10 of RI for WKY+RI+ candesartan (collateral-dependent/normal zone flow ratio at day 10 of RI was 0.58) versus 0.13±0.02 mL/min/g on day 0 to 0.84±0.02 mL/min/g on day 10 of RI for WKY+RI (collateral-dependent/normal zone flow ratio at day 10 of RI was 0.84; Figure 1).
Because candesartan decreased blood pressure, we used the Ca2+ channel blocker dilitiezem hydrochloride (30 mg/ kg/d) to reduce blood pressure without effecting AT1R-dependent signaling to ascertain whether the effect of candesartan on CCG was blood pressure–dependent. Dilitiezem hydrochloride reduced blood pressure to levels comparable to reduction by candesartan (85±7 mm Hg in WKY; 114±11 mm Hg in JCR), but had no significant effect on CCG (WKY+RI+dilitiziem chloride 0.78±0.06 mg/min/g; JCR+RI+dilitiziem chloride 0.21±0.08 mg/min/g on day 10 of RI; please see the supplemental materials, available online at http://atvb.ahajournals.org).
Subpressor Dose of Ang II Augments CCG in WKY Rats, but Hypertensive Dose Compromises It
WKY animals were given either a subpressor dose of Ang II (0.3 mg/kg/d), which did not alter blood pressure (110±9 mm Hg), or a hypertensive dose of Ang II (0.7 mg/kg/d), which significantly increased blood pressure (139±9 mm Hg) via osmotic minipumps for 14 days. RI+subpressor Ang II caused an increase in collateral-dependent zone flow which was significantly greater than that achieved by RI alone (0.13±0.02 mL/min/g on day 0 to 1.24±0.03 mL/min/g on day 10 of RI for WKY+RI+sub-pressor Ang II [collateral-dependent/normal zone flow ratio at day 10 of RI was 1.12] versus 0.13±0.02 mL/min/g on day 0 to 0.84±0.02 mL/min/g on day 10 of RI for WKY+RI collateral-dependent/normal zone flow ratio at day 10 of RI was 0.84; Figure 2). In contrast, RI+hypertensive Ang II–induced increase in collateral-dependent zone flow was significantly less than that achieved by RI alone (0.12±0.01 mL/min/g on day 0 to 0.69±0.01 mL/min/g on day 10 of RI for WKY+RI+ hypertensive Ang II [collateral-dependent/normal zone flow ratio at day 10 of RI was 0.69] versus 0.13±0.02 mL/min/g on day 0 to 0.84±0.02 mL/min/g on day 10 of RI for WKY+RI [collateral-dependent/normal zone flow ratio at day 10 of RI was 0.84]; Figure 2). Thus, whereas subpressor Ang II augments RI-induced CCG, hypertensive Ang II is detrimental.
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Ang II Regulates CCG in Part via AT1R-Dependent Regulation of ROS Concentrations and ROS-Sensitive and Time-Specific p38 and Akt Activation
To elucidate the molecular signaling mechanisms by which Ang II may regulate CCG, we investigated the effect of AT1R blockade, subpressor, and hypertensive Ang II on myocardial superoxide levels and p38 and Akt activation. Myocardial superoxide was assessed qualitatively by DHE (please supplemental materials) and quantitatively by X-band EPR (Figure 3). Basal, non–ischemia-induced superoxide production was significantly higher in JCR versus WKY animals (0.5±0.01 versus 0.1±0.02; Figure 3). AT1R blockade by candesartan decreased superoxide levels in the collateral-dependent zone of both JCR (0.4±0.2 versus 2.3±0.4 nmol/L, n=3, P<0.05) and WKY (0.1±0.04 versus 0.6±0.05 nmol/L, n=3, P<0.05) animals (Figure 3). Subpressor Ang II resulted in generation of a slightly higher level of superoxide in the collateral-dependent zone compared with that induced by RI alone (0.8±0.02 versus 0.6±0.05 nmol/L n=3, P<0.05). Treatment with hypertensive Ang II resulted in a large increase in superoxide (1.9±0.3 versus 0.8±0.02 nmol/L, n=3, P<0.05; Figure 3). All treatments resulted in superoxide level alterations in the normal zone; however, although significant, the magnitude of change was smaller in the normal zone than in the collateral-dependent zone in all groups (Figure 3).
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Candesartan restored p38 (4.8±0.1-fold [RI+candesartan] versus 0.95±0.3-fold [RI] versus sham [1±0.2]) and Akt activation (2.6±0.2-fold [RI+candesartan] versus 1.2±0.2 fold [RI] versus sham [1±0.35]) in JCR, but blocked p38 (1.1±0.2 fold [RI+candesartan] versus 3.4±0.35 fold [RI]) and Akt activation (1.8±0.4 fold [RI+candesartan] versus 4.85±0.02 fold [RI]) in the collateral-dependent zone of WKY animals at the point of their maximal activation in WKY animals (day 3 of RI; Figure 4). p38 and Akt were not activated in the normal zone and their expression was not altered in the collateral-dependent zone or the normal zone of any group (data not shown).
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We have recently shown that p38 was transiently activated by RI in WKY rats, which was permissive to CCG.7 Because transient p38 activation has been reported to promote angiogenesis in cancer,13 whereas sustained activation was inhibitory,17 and Akt is required for cell survival,11,12 a process necessary for either angiogenesis or collateral growth, we hypothesized that duration of p38 and Akt activation may also correlate with the permissive versus inhibitory effects of Ang II on CCG, and investigated the effect of subpressor Ang II and hypertensive Ang II on the extent and duration of p38 and Akt activation (Figure 5). Subpressor Ang II caused transient p38 (day 3 only) and sustained Akt activation (days 3 to 9 of RI). In contrast, treatment with hypertensive Ang II resulted in sustained p38 (days 3 to 9 of RI) but transient Akt activation (decreased 2±0.2-fold on day 6 versus 3.5±0.25 fold on day 3, blocked on day 9 of RI; Figure 5). Interestingly, AT1R blockade by candesartan restored transient p38 activation but failed to elicit sustained Akt activation (Figure 4).
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Discussion
The major finding in this study is that AT1R blockade in WKY rats is detrimental to CCG, whereas AT1R blockade in JCR rats partially restores CCG. Furthermore, in WKY animals, treatment with a nonhypertensive Ang II further increases CCG, but treatment with a hypertensive Ang II abrogates CCG. Importantly, we show that the molecular basis of these disparate effects of Ang II is at least in part related to its regulation of myocardial oxidative stress. Finally, we demonstrate that both extent and duration of p38 and Akt activation are important regulators of CCG and provide at least a partial molecular mechanisms for the disparate effects of Ang II and AT1R blockade in healthy versus metabolic syndrome or hypertensive animals.
In support of the present study, it has been reported that short and repetitive exposure to hypoxia/reoxygenation produces ROS that are associated with angiogenesis and collateral growth.18–20 We have recently shown that RI-induced CCG is critically dependent on an optimal concentration of myocardial ROS.7 Furthermore, we have recently shown that in another rat model where CCG is compromised, the ZOF rat, lowering oxidative stress was required for restoration of CCG in response to VEGF, when VEGF alone did not induce CCG.8
Ang II potently activates myocardial and vascular NAD(P)H oxidases,21 which are major producers of ROS in the vascular wall and the myocardium.21,22 The complication of previous studies investigating the effect of ACE inhibition or AT1R blockade on angiogenesis and collateral growth and arriving at opposite conclusions regarding detrimental5,6 versus beneficial4 role of Ang II in these processes is that they did not measure oxidative stress. Our results demonstrate that the level of myocardial oxidative stress at the onset of treatment with AT1R blockers is directly related to their effect on CCG. We show that basal and RI-induced oxidative stress is markedly higher in JCR versus WKY rats (Figure 3), and that although oxidative stress induced by RI in WKY animals is associated with CCG, the level induced by RI in JCR rats is too high and not permissive for CCG (Figure 1). Importantly, we show that AT1R blockade by candesartan in JCR partially restored CCG (Figure 1). These results are in agreement with previous studies showing that enalapril and losartan increased non–ischemia-induced myocardial angiogenesis in the ZOF rat6 and ischemia-induced hind limb collateralization in diabetic mice.23 The effect of candesartan was associated with lowering RI-generated myocardial superoxide levels to an amount similar to that elicited by RI in WKY animals and permissive for CCG (Figure 3). In contrast, AT1R blockade in WKY animals abrogated CCG (Figure 1). These results are in agreement with a previous report that AT1R blockers inhibited angiogenesis in the retina.23 Like in JCR rats, candesartan lowered superoxide, but because of lower initial levels in WKY animals, to a level that is too low for CCG and comparable to that observed in sham animals (Figure 3). Thus, we believe that regulation of myocardial oxidative stress is a key determinant of CCG. Our results further show that subpressor Ang II in WKY animals increased CCG above the increase achieved by RI alone and was associated with a slight elevation in myocardial oxidative stress, whereas hypertensive Ang II decreased CCG and was associated with a large increase in oxidative stress comparable to that induced by RI in JCR animals, which was detrimental for CCG (Figure 3). RI, and treatment with candesartan, subpressor, and hypertensive Ang II also altered superoxide levels in the normal zone. We believe that this relates to the phenomenon of remote preconditioning and note that these alterations in the remote myocardium were smaller in magnitude than in the collateral-dependent zone, and did not extend to alterations in ROS-dependent signaling.
Because candesartan also lowered blood pressure, we used a Ca2+ channel blocker, dilitiezem hydrochloride to lower blood pressure without effecting AT1R-dependent ROS production and signaling. Dilitiezem hydrochloride decreased blood pressure to values comparable to those achieved by candesartan but did not have a significant effect on CCG in either WKY or JCR animals. We conclude that the effect of AT1R blockade on RI-induced CCG is blood pressure–independent. This is in agreement with HOPE clinical trials which show beneficial effects of ACE inhibition on myocardial infarction, stroke, and total cardiovascular-related death in nonhypertensive type II diabetic patients.24
We have recently shown that repetitive myocardial ischemia activated p38 and that its activation was required for CCG.7 Here, we show that where CCG occurs, p38 and Akt are both activated but p38 activation is transient whereas Akt activation is sustained. In contrast, where CCG does not occur or is compromised, p38 and Akt are either not activated or the duration of their activation is altered so that p38 activation becomes sustained and Akt activation transient. Neither p38 nor Akt are activated in JCR on day 3 of RI, the time point of their maximal activation in WKY (Figure 4). We believe that this is because, whereas in WKY animals RI induces levels of oxidative stress necessary for activation of these redox-sensitive kinases, in JCR animals, RI induces levels of oxidative stress which are so high that they inhibit their activation. High levels of ROS can inhibit ROS-dependent signaling in several ways, including direct modification by thiol oxidation, oxidized thiol nitrosylation, and tyrosine nitrosylation of upstream regulators, which prevent kinase phosphorylation (activation) or by proteolytic cleavage of upstream regulators.25,26 Because both Akt and p38 have been shown to be involved in cell survival,11,12 proliferation,13 and migration,14,15 processes necessary for CCG, this lack of activation in JCR animals is not surprising. AT1R inhibition blocks p38 and Akt activation in WKY animals (Figure 4). This is not surprising because both p38 and Akt have been shown to be activated by Ang II.9,10 Moreover, activation of both kinases is dependent on low amount of ROS in cultured vascular smooth muscle cells,9,10 and we have previously demonstrated that ROS are required for p38 activation in cultured coronary endothelial cells in response to VEGF and in response to RI in vivo; lowering of myocardial superoxide and hydrogen peroxide concentrations to levels too low for CCG also blocked p38 activation.7 Interestingly, candesartan treatment restored p38 and Akt activation in JCR animals. These results may seem paradoxical because activation of both is AT1R-mediated. We believe that the effect of candesartan in JCR animals may be related to a requirement for a specific, neither too low nor too high, amount of ROS for p38 and Akt activation. Thus candesartan-madiated reduction in oxidative stress, where basal and RI-induced oxidative stress is elevated (JCR) may explain its positive effect on p38 and Akt activation. The present study however does not include a complete dose response to varying amounts of ROS. This precludes a conclusive interpretation of our results.
Finally, our results show that the duration of activation of both kinases is equally critical. In WKY rats, RI alone, and treatment with Ang II was associated with transient p38 and sustained Akt activation (Figure 5). Similarly, candesartan treatment in JCR rats restored p38 activation only on day 3 of the RI protocol. In contrast, treatment with hypertensive Ang II was associated with sustained p38 and transient Akt activation (Figure 5). Our results are supported by studies in cancer angiogenesis. A unique feature of p38 activation is that it is both pro-13 and antiangiogenic17 in vitro. Specifically, its early and transient activation promoted the acquisition of a malignant migratory phenotype and tumor angiogenesis,13,27,28 whereas prolonged activation lead to cell death and blocked tumor angiogenesis.17 Angiogenesis and collateral growth are distinct processes, and direct translation of findings from one to the other is problematic; however, based on our results, and because basic cellular responses, including survival, proliferation, migration, and extracellular matrix degradation are necessary for both processes and are regulated by p38 and Akt in culture, we believe that at least with respect to ROS-sensitive signaling, such a comparison may be relevant. To our knowledge, the duration of Akt activation with regards to angiogenesis has not been studied; however, sustained Akt activation is well-known to be required for cell survival.11,29 Interestingly, it has been reported that PI3-kinase/Akt activation might in fact downregulate p38 activation in endothelial cells and that this event protects cells from p38-mediated apoptosis.12 Although candesartan treatment did activate Akt in JCR rats, it was not able to elicit sustained Akt activation. This could offer partial explanation for the mechanistic basis of incomplete restoration of CCG in JCR in response to AT1R blockade and may speak to the critical role for ROS-sensitive signaling in the regulation of CCG.
Elevated oxidative stress is a hallmark of pathologies which are risk factors for coronary disease, including hypertension and Syndrome X. The most critical finding in this study, that Ang II has opposite effects on CCG depending on the level of myocardial oxidative stress, in addition to our observation that Ang II specifically regulates both activation and duration of activation of p38 and Akt, provides an important insight into the molecular mechanisms of Ang II–mediated CCG. Apart from regulation of ROS production and ROS-sensitive signaling, Ang II has a wide variety of effects on vascular growth and remodeling which may impact CCG, including ROS-insensitive signaling activation. Possible AT1R-mediated but ROS-independent events which may regulate CCG are beyond the scope of the present study and currently limit the applicability of our findings to clinical treatment involving AT1R blockers.
Acknowledgments
Sources of Funding
This work was supported by American Heart Association grant 0630285N and National Institutes of Health grants RR018766 and 32788.
Disclosures
None.
Footnotes
Original received August 22, 2007; final version accepted October 15, 2007.
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