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COX-2 Suppression and statins

EXCELLENT   This article solves the mystery as to why statins greatly improve cholesterol profile, yet have a net no benefit as to extending life.  All COX-2 inhibitors increase dramatically atherogenesis and thus cardiovascular disease but for aspirin.  Suppression of COX-2 counters the positive cholesterol profile.  It is like taking Vioxx with niacin.   On top of that it reduces the molecule of energy, ATP, by reducing the production of CoQ10 there is a major increase in death from cardiac heart failure (the heart muscle’s lack of energy to meet the bodily requirement for oxygenated blood).   (sited in 161 journal articles) 


Suppression of the Functionally Coupled Cyclooxygenase-2/Prostaglandin E Synthase as a Basis of Simvastatin-Dependent Plaque Stabilization in Humans

Francesco Cipollone, MD; Maria Fazia, PhD; Annalisa Iezzi, PhD; Mirco Zucchelli, PhD; Barbara Pini, MD; Domenico De Cesare, Tch; Sante Ucchino, MD; Francesco Spigonardo, MD; Guido Bajocchi, MD; Roberto Bei, MD; Raffaella Muraro, MD; Luciano Artese, MD; Adriano Piattelli, MD; Francesco Chiarelli, MD; Franco Cuccurullo, MD; Andrea Mezzetti, MD

Background—The clinical benefits of statins are attributed to changes in plaque composition that lead to reduced metalloproteinase (MMP) activity and plaque stabilization. However, the molecular mechanism of this effect is unclear.  Recently, we demonstrated enhanced expression of isoforms of inducible cyclooxygenase (COX) and PGE synthase (COX-2/mPGES) in human symptomatic plaque and provided evidence that this is associated with MMP-induced plaque rupture. The aim of this study was to characterize the effect of simvastatin on inflammatory infiltration and the expression of COX-2/mPGES and MMPs in human carotid plaques.

Methods and Results—Seventy patients with symptomatic carotid artery stenosis were randomized to the American Heart Association Step 1 diet plus simvastatin (40 mg/d) or the American Heart Association Step 1 diet alone for 4 months before endarterectomy. Plaques were subjected to analysis of COX-1, COX-2, mPGES, MMP-2 and MMP-9, lipid and oxidized LDL (oxLDL) content, and collagen content by immunocytochemistry, Western blot, and reverse transcription–polymerase chain reaction, whereas zymography was used to detect MMP activity. Immunocytochemistry was also used to identify CD68 macrophages, CD3 T-lymphocytes, smooth muscle cells (SMCs), and HLA-DR inflammatory cells. Plaques from the simvastatin group had fewer (P0.0001) macrophages, T-lymphocytes, and HLA-DR cells; less (P0.0001) immunoreactivity for COX-2/mPGES and MMPs; reduced (P0.0001) gelatinolytic activity; increased (P0.0001) collagen content; and reduced (P0.0001) lipid and oxLDL content. Interestingly, COX-2/mPGES inhibition by simvastatin was completely reversed by mevalonate in vitro. 

Inflammatory processes play a pivotal role in the pathogenesis of atherosclerosis, particularly in the progression of atherosclerotic plaque toward instability.  Rupture-prone lesions contain a large lipid core underlying a thin and collagen-poor fibrous cap, and they usually have prominent inflammatory infiltrates of macrophages and lymphocytes. Macrophages produce proteolytic enzymes capable of degrading plaque constituents, including members of the etalloproteinase (MMP) family. In particular, expression of MMP-2 and MMP-9 has been shown within human atherosclerotic lesions and critically implicated in plaque rupture.

Conclusions—This study demonstrates that simvastatin decreases inflammation and inhibits COX-2/mPGES expression in plaque macrophages, and this effect in turn may contribute to plaque stabilization by inhibition of MMP-induced plaque rupture. (Circulation. 2003;107:1479-1485.  {This article fails to consider the VIGOR study, or the growing literature on how COX-2 promotes atherosclerosis}

Production of these MMPs by macrophages occurs through a prostaglandin (PG) E2 -dependent pathway.  Signaling through this pathway involves the modulation of cyclooxygenase (COX) and PGE synthase (PGES). Two isoforms of COX (COX-1 and COX-2) and PGES (cPGES and mPGES) have been identified. COX-1 and cPGES are constitutively expressed. In contrast, COX-2 and mPGES are induced in response to several stimuli in inflammatory diseases. Consistent with the hypothesis of COX-2/mPGES contributing to the clinical instability of atherosclerosis, we have recently reported the overexpression of COX-2/mPGES as a pathway underlying the enhanced release of active MMPs in symptomatic atherosclerotic plaques.

Hypercholesterolemia is a major risk factor for atherosclerosis, and recent clinical trials have shown that statins reduce cardiovascular events and mortality in humans. Clinical benefits of statins are greater than those expected on the basis of the modest change in arterial stenosis severity. These data suggest that statins may somehow stabilize plaques against disruption.

In this regard, it is of extreme interest to analyze the ability of statins to reduce gelatinolytic activity. Crisby et al recently demonstrated that statins may decrease inflammation and MMP-2 and increase collagen content in human carotid plaques. However, the specific molecular mechanisms by which statins may influence MMP generation in plaque macrophages are still unknown.

The possibility that the suppression of COX-2 and mPGES by statins might represent a mechanism of plaque stabilization led us to investigate whether it would modulate MMP production by macrophages into atherosclerotic plaques.  Here, we report reduced MMP production by macrophages in carotid plaques of patients randomized to simvastatin, most likely because of a reduction in PGE2 synthesis as a result of the suppression of COX-2/mPGES.



 We studied 70 of 128 consecutive surgical inpatients who had been enlisted to undergo carotid endarterectomy for  extracranial highgrade (70%) internal carotid artery stenosis. All patients were symptomatic according to North American Symptomatic Carotid Endarterectomy Trial classification and had LDL cholesterol (LDL-C) ranging between 100 and 129 mg/dL. Patients were randomized to 4-month treatment with the American Heart Association Step 1 diet plus simvastatin (Sinvacor, Merck Sharp & Dohme) 40 mg/d or American Heart Association Step 1 diet alone. After the treatment period, all patients underwent endarterectomy. Fasting plasma total cholesterol, HDL cholesterol, LDL-C, and triglyceride levels were measured at baseline and before endarterectomy. Procedural methods, risk factors, and concomitant therapy did not differ between the 2 groups (Table 1). By the time of surgery, all patients were taking 100 mg of aspirin daily, a dose that does not affect vascular COX-2 because of rapid de novo synthesis of the enzyme in nucleated cells during the 24-hour dosing interval. The study was approved by local ethics review committees. Written informed consent was obtained from all patients before each examination.


Samples were frozen in isopentane and cooled in liquid nitrogen.  Serial sections were prepared as described previously and incubated with the specific antibodies anti-CD68, anti-CD3, anti-HLA-DR, anti--smooth muscle actin, and anti-CD31 (Dako Corporation); anti-COX-1, anti-COX-2, and anti-mPGES (Cayman Chemical); anti-MMP-2 and anti-MMP-9  (Calbiochem-Novabiochem); and anti-oxLDL (a gift from Dr Raffaella Muraro). In addition, 4 sections from each plaque were examined for the presence of plaque ulceration and intraplaque hemorrhage. The specimens were analyzed by an expert pathologist (intraobserver variability 6%) blinded to the patient’s therapy.  Quantitative Analysis for Histology CD3-positive T cells were counted individually and expressed as the number of cells per square millimeter of section  area as determined by computer-aided planimetry (see below). Furthermore, we determined the area occupied by CD68-positive and -actin–positive cells planimetrically and calculated the percentage of macrophage-rich and smooth muscle cell (SMC)–rich areas. Analysis of experiments was performed with a PC-based 24-bit color image-analysis system.  In brief, electronic images were digitized with a Leica CCD DC100 color video camera into a 1 kilopixel

1 kilopixel image buffer of the AlphaEase 5.02 image analysis system (Alpha Innotech Corp). A color threshold mask for immunostaining was defined to detect the red color by sampling, and the same threshold was applied to all specimens. The percentage of the total area with positive color for each section was recorded. 


TABLE 1. Characteristics of Study Patients

Variable                                                            Control (n

35)                     Simvastatin (n

Age, y                                                                71                                                        72          

Male/female                                                   18 - 17                                                19 -16

Patients with:                                                                                                                                                                                         ;

Recent TIA and stroke                                  35                                                        35

Family history of IHD                                     18                                                        16

Hypertension                                                   25                                                        23

Diabetes                                                           12                                                        13

Cigarette smoking                                          19                                                        18

NSAID or glucocorticoid treatment            0                                                           0

Stenosis severity, %

Mean  +/-SD                                                    76 +/-6                                               77 +/-8

Range                                                                70–93                                                 70–95

Percentage of macrophage-rich areas      26 +/-11*                                          8 +/-5

Number of T cells per mm2 section area 71 +/-21*                                            23 +/-11

Percentage of SMC-rich areas                     19 +/-8+                                                            15 +/-6

TIA indicates transient ischemic attack; IHD, ischemic heart disease; and NSAID, nonsteroidal antiinflammatory drug.  *P0.0001; †P0.03.

_____details left out, see journal at



Percentages of carotid diameter reduction did not differ between the 2 groups (1.11.4% versus 0.81.1%).  Baseline lipid levels were similar in the 2 groups (Table 2).  At the end of the study, total cholesterol and LDL-C levels were significantly reduced in patients treated with simvastatin (30% and 41%, respectively), whereas they did not change in patients randomized to diet alone (Table 2). No patient in either group developed any clinical events during the study.

. . . . . . . .

COX-2 Expression in Plaques Is Reduced

by Simvastatin

After treatment, COX-2 was more abundant in control lesions than in plaques from simvastatin-treated subjects (23.25.2% versus 6.12.2%, n

35; P0.0001; Figure 2). COX-2 accumulated in the activated macrophages at the shoulder region in control subjects, whereas it was localized primarily in SMCs in simvastatin-treated patients. Finally, Western blot and reverse transcription–polymerase chain reaction analyses (Figure 3) confirmed markedly lower COX-2 expression in simvastatin-treated plaques (6158152 versus 1236321 densitometric units [DU] for protein expression, n
35; P0.0001). In contrast, no significant effects were observed with respect to COX-1 expression (Figure 2).

mPGES Expression in Plaques Is Reduced by Simvastatin

Immunohistochemistry revealed strong mPGES immunoreactivity in all of the control plaques but only weak staining in the simvastatin-treated plaques (19.63.2% versus 3.71.3%, n

35; P0.0001; Figure 2). In the control group, mPGES localized in the plaque shoulder, an area characterized as macrophage rich. Only weak mPGES expression was observed by Western blot in simvastatin-treated plaques (Figure 3). In contrast, a 5-fold higher signal was demonstrated in control plaques (946265 versus 5163194 DU, n
35; P0.0001).

Effect of Simvastatin on MMP Expression in Plaques

MMP staining was significantly less abundant in lesions from simvastatin-treated patients than in controls (Figure 2). Levels of MMP-2 and MMP-9 in control plaques (24.64.7% and 26.25.6%, respectively; n

35) significantly exceeded (P0.0001) those in simvastatin-treated plaques (6.41.9% and 7.22.5%, respectively; Table 1). Immunoreactivity localized in the plaque shoulder, corresponding to areas of intense macrophage infiltration. Effect of Simvastatin on MMP Activity in Plaques The higher (P0.0001) MMP-2 and MMP-9 immunoreactivity documented by Western blot in control plaques (6231284 versus 1894187 and 6745421 versus 2745 +/-347 DU, respectively; n
35; Figure 4A) does not necessarily correspond to enhanced enzymatic activity, because all MMPs require activation before they can digest their substrate.  Thus, we used zymography to demonstrate that control plaques contained activated MMPs (Figure 4B). In contrast, only weak positivity for activated MMPs was observed in simvastatin-treated plaques (Figure 4B). Thus, the amount of inactive and active MMP-2 (5247285 versus 1145 +/-275 and 2874 +/-302 versus 598 +/-124 DU, respectively;   n =35) and MMP-9 (6136 +/-368 versus 1321 +/-354 and 2645641 versus 876221 DU, respectively) was significantly higher (P0.0001) in the control plaques. 

Effect of Simvastatin on Plaque

Extracellular Components Sirius red polarization showed increased collagen content in the sections of simvastatin-treated patients compared with control patients (15.23.4% versus 8.13.8%, n

35; P0.0001). In contrast, the plaque content of lipid (Figure 5A) and oxLDL (Figure 5B) was significantly reduced after simvastatin therapy (27.2 +/-11.5% versus 6.9 +/-4.1% and 25.3 +/-5.8% versus 10.7 +/-2.8%, respectively; n
35; P<0.0001)


We have previously reported that COX-2 and mPGES contribute to the clinical instability of atherosclerotic plaques by promoting plaque rupture induced by MMPs, key enzymes in the final step of this process. Now, in the present report, we provide evidence for the critical involvement of COX-2/mPGES in the process of plaque stabilization induced by simvastatin therapy. The present findings are the first, to the best of our knowledge, to (1) demonstrate by randomized study the anti-inflammatory effect of statins in human carotid atherosclerotic plaques, (2) show a direct inhibitory effect of simvastatin on COX-2/mPGES in human atherosclerotic lesion, and (3) relate the inhibition of COX-2/mPGES to the reduction of MMP activity observed after statin therapy.

Concomitantly higher expression of COX-2/mPGES, MMP-2, and MMP-9 was found in specimens obtained from the culprit carotid lesions of patients randomized to diet alone compared with specimens obtained from patients randomized to simvastatin. In particular, all plaques obtained from simvastatin-treated patients exhibited only weak positivity, whereas only 3 (8.5%) of 35 plaques randomized to diet alone demonstrated intensity of enzyme expression comparable to that observed in simvastatin-treated plaques. Notably, the positive impact of statin-dependent MMP suppression was confirmed by the parallel increment in plaque collagen content after simvastatin therapy. In the present study, macrophages were more abundant in control plaques, always outnumbered the lymphocytes, and  represented the major source of COX-2/mPGES and MMPs. Furthermore, the site of inflammatory infiltration in control plaques was always characterized by strong expression of HLA-DR antigens on inflammatory cells, which contrasted with the low expression of HLA-DR elsewhere in the simvastatin-treated plaques. These data suggest the ability of simvastatin to reduce the inflammatory reaction in symptomatic plaques. In fact, in agreement with the difference in COX-2/mPGES and MMP staining pattern, the histological milieu of the lesions appears different with regard to cellularity, presence of foam cells, cholesterol clefts, and collagen content but not in the degree of vessel stenosis, which suggests that lesions treated with simvastatin or diet alone are different only with regard to inflammatory burden and that differences in plaque behavior stem from differences between simvastatin and diet alone in the ability to influence the expression of 1 or more proteins capable of disrupting plaque stability.

Previous studies have reported the ability of statins to reduce atherosclerotic lesion evolution toward rupture.  However, these studies did not provide any evidence about the involvement of COX-2/mPGES in the pathophysiology of simvastatin-dependent plaque stabilization. COX-2 is an intermediate enzyme in the metabolic pathway of arachidonic acid, and the COX bioproduct PGH2 is further metabolized by other isomerases to various prostanoids. Thus, the relative abundance of a specific prostanoid rather than another is the result of the expression and activity of its specific  somerase, and the concomitant expression of functionally coupled COX-2/mPGES is necessary for the biosynthesis of PGE2 - dependent MMPs in the setting of atherosclerotic plaque. Interestingly, because macrophages of the shoulder region contain most of the COX-2/mPGES protein within the lesion, they emerge as the principal cellular target of simvastatin in the context of plaque stabilization. This finding may have functional importance and may contribute to explain the controversial experimental and clinical findings associated with selective COX-2 inhibition, because different cell types can regulate the production of different eicosanoids. Endothelium predominantly releases PGI2 , an inhibitor of platelet activation and cholesterol accumulation, and Belton et al reported that COX-2 is responsible for the increase in PGI2 seen in patients with atherosclerosis. In contrast, macrophages, not present in normal arterial tissue, produce an array of prostanoids, including PGE2 , considered one of the most atherogenic eicosanoids.

Prostanoids have potent actions on SMCs, regulating contractility, cholesterol metabolism, and proliferation. Reduced expression of COX might thus contribute to the decrease of lipid accumulation in lesional SMCs (and macrophages), reducing formation of SMC- and macrophage-derived foam cells within atheroma. On the other hand, antiproliferative and antimigratory actions of COX products on SMCs suggest potential contributions of the inhibition of this enzyme to the evolution of a lesion toward an SMC-enriched and macrophage-depleted, and thus more stable, plaque.  Furthermore, COX-2 can modulate angiogenesis by synthesis of angiogenic factors and neovessel formation.  consequently, COX-2 inhibition within the lesion contributes to the reduction of new blood vessel formation, thus inhibiting plaque expansion. More importantly, PGE2 , a predominant eicosanoid of macrophages, induces in human atherosclerotic plaques the expression of MMP-2 and MMP-9, enzymes considered crucial in the degradation of plaque stability. Our description of a strong reduction of these MMPs in plaque treated with simvastatin and found to be macrophagedepleted and COX-2/mPGES-negative suggests that such arachidonate-dependent inhibition of MMPs by simvastatin may operate in vivo. Interestingly, these data obtained in patients with only modest increments in LDL-C are in accord with the results of the recent Heart Protection Study and provide further support against the existence of an LDL-C threshold below which reductions would not reduce risk. The present results are partially in agreement with Crisby et al because they demonstrate reduced MMP-2 activity in statin-treated plaques. However, in the present study, simvastatin also significantly reduced MMP-9 activity and increased the plaque content of SMCs, whereas in the study by Crisby et al, pravastatin failed to obtain these results. Several hypotheses could be raised to explain these conflicting data. First, the study by Crisby et al, despite being well designed, was a nonrandomized study, and thus, hidden biases could explain the different results. Alternatively, the different statin used, the stronger lipid-lowering effect, or the  longer period of treatment might all contribute to explain the observed differences.

The present report is also in accord with recent in vitro evidences demonstrating that atorvastatin may reduce inflammation by decreasing COX-2 expression in SMCs, although it differs from the report of Degraeve et al, which showed that mevastatin and lovastatin may upregulate COX-2 expression in SMCs in vitro. These contradictory data suggest that different statins may exert diverse effects on the complex signal transduction pathways involved in COX-2 regulation.

In the present study, the hypothesis that plaque COX-2/ mPGES suppression by simvastatin was largely dependent on the reduction in plaque cholesterol was supported by the in vitro experiments with mevalonate and by the observation that reduction of COX-2/mPGES in plaque was associated with comparable reduction in oxLDL content. However, further studies directly comparing simvastatin with other lipid-lowering strategies are necessary to definitively answer this question.

In conclusion, the present study addresses the missing link between statin therapy and MMP inhibition that leads in turn to plaque stabilization, by demonstrating the inhibition of thefunctionally coupled COX-2/mPGES in human atherosclerotic lesions after simvastatin therapy and providing evidence that downregulation of COX-2/mPGES in activated macrophages by simvastatin is associated with plaque stabilization, possibly by suppression of MMP-induced matrix degradation, which promotes plaque rupture. These findings are potentially important from a fundamental standpoint because they indicate a crucial role for inducible COX/PGES in the stabilization of atherosclerotic lesions observed with statins. From a practical standpoint, these findings provide further support for the possibility that statins might provide a novelform of therapy for plaque stabilization in patients with atherosclerotic disease.


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Those who have a financial interest in the outcome manipulate the results, Major study finds that all 37 journal articles positive effects over stated; the average was 32%. Statins cause erectile dysfunction, cognitive imparement, and cancer.  

Lipitor (2011) lifetime sales $131 billion, tops all drugs.  Plavix at $60 billion is second.



52% short term


LA Times, Health section, July 21, 2008  --  excerpts

Vytorin, the combination drug (simvastatin (better known by its commercial name Zocor) and ezetimibe--known as Zetia) prescribed to lower cholesterol, sustained another blow today, when the author of a major clinical trial announced that the medication had failed to drive down hospitalization and death due to heart failure in patients with narrowing of the aortic valve. In the process, researchers in Norway detected a significant blip in cancers in the 1,800 subjects they followed

Today's findings suggested something more ominous: the incidence of cancer -- and of dying of cancer -- was significantly higher in the patients taking Vytorin. Altogether, 67 patients on placebo developed cancer during the trial. Among subjects on Vytorin, 102 developed cancers of various kinds.*  This is the second adverse press—the first being in March 08, when the ENHANCE trial found that Vytorin fared no better than a placebo at reducing plaque buildup on the walls of patients' arteries.* *

Comments by jk

Simvastatin (Zocor) is off patent.  Thus in a scramble for profits a combination drug (on patent) was introduced.  Direct to consumer market cost $155 in 07—mainly TV ads. 

*  The pressing issue is that since the development  of Statins, the very first animal studies in the 60s it has been known that Statins increase the incidents of cancer.  However, nearly all studies done thereafter have not included cancer. 

*  Several studies have failed to find a reduction in the build of plaque, even thought the statins including Zocor, reduce LDL and cholesterol.  Few studies include the principle reason for taking a statin, namely a reduction in the death rate.  Claims for such reduction probably entail a failure to control the contravening variable, aspirin usage.  Given a pile of evidence, including the very mechanism of plaque formation, which involves inflammation process, I must conclude that the use of statins is highly suspect.  Given the harm done including cognitive impairment, weakness, and cancer, if my skepticism is born out, the harm done by statins as a course of treatment will far surpass that of VIOXX which killed over 200,000 people world wide by accelerating atherosclerosis.