John Steele Taylor

November 14, 2007

Pharmacology 201

Lifestyle Factors and Pharmacological Agents that Manage Hyperlipidemia

Through Activation of Peroxisome Proliferator Activated Receptors

Part 1: Introduction and Overview

This paper concerns a specific class of drugs used in the treatment of

hypertriglyceridemia and hypercholesterolemia that operate through activating a class of

transcriptional activators known as peroxisome proliferator activated receptors (PPARs).

PPARs are transcriptional activators distributed throughout a diversity of tissues that

operate through orchestrated mechanisms primarily to regulate carbohydrate and lipid

metabolism. Therefore, these transcriptional activators play a central role in treatment of

atherosclerotic diseases and general metabolic syndromes that are highly prevalent in

western populations. Clinical and epidemiological studies have thoroughly established a

definite correlation between atherosclerotic related events and certain serum lipid

profiles. These serum lipid profiles represent independent risk factors; however, they

often accompany insulin resistance and other features of metabolic syndrome.

Due to the complexity of factors and pathways involved in lipid metabolism and

the pathogenesis of atherosclerosis, an introductory section is included to summarize

these mechanisms for the lay-reader. Additionally, mechanisms through which diet and

exercise regiments can favorably influence serum lipid profile and prevent atherosclerosis

will be discussed at considerable length, both for the purpose of emphasizing their role as

a first line of treatment and for elucidating some of the mechanisms that are targeted by

the drugs discussed later in this paper. Once this has been accomplished, a second stand-

alone section is devoted entirely to the discussion of PPAR activating drugs, including

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proposed mechanisms of action, pharmacokinetic considerations, and adverse

effects/toxicities.

Lipoprotein Metabolism: Normal and Dysfunctional

The transport of cholesterol and triglycerides through the bloodstream is

complicated by the fact that these are hydrophobic molecules that need to be moved

through a watery environment. Transport is therefore achieved through packaging lipids

into lipoproteins, which have the general characteristic of having a protein hydrophilic

outer layer and a lipid core (hence the name lipo-protein). Three important outer

proteins, or apoproteins, will be considered in this paper and include apoprotein-A1 (apo-

A1), apoprotein-B-100 (apo-B-100), and apoprotein C-3 (apo-C3). These apoproteins are

discretely associated with certain lipoproteins and are major determinants in the

characteristics and function of these lipoproteins. Regulation of apoprotein expression,

degradation, and exchange is an important drug target due to their influence on

mechanisms involved in the development of arterial diseases (1).

Two pathways of lipoprotein metabolism exist: an exogenous pathway where

dietary triglycerides and cholesterol are packaged into chylomicrons in the intestinal

mucosaand distributed throughout the circulation; and an endogenous pathway where

triglycerides and cholesterol are packaged in to lipoproteins in the liver for distribution

through the bloodstream. The endogenous pathway is our primary concern, especially

due to the fact that a major fate of chylomicrons in post-prandial (post-meal) metabolism

is hepatic conversion into very-low-density-lipoprotein (VLDL), which are the primary

endogenous triglyceride transporter, (2).

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 Circulating VLDLs are hydrolyzed by lipoprotein lipase (LPL), an enzyme fixed

on the luminar surface of vascular endothelium, into free fatty acids (FFAs) for uptake

into muscle and adipose tissue. VLDL is converted to intermediate-density-lipoprotein

(IDL) as it releases FFAs. IDL has two fates: degradation in the liver and conversion to

low-density lipoprotein through donating apolipoprotein C-II (Apo-C2) to high density

lipoproteins (HDL). In this manner, increasing LPL activity causes a decrease in VLDL

and an associated increase in HDL. This pathway is a major drug target. (2).

Low density lipoprotein (LDL) is responsible for the transfer of cholesterol to

peripheral tissues for utilization in numerous functions including membrane synthesis and

steroid hormone production. Under normal conditions most of the circulating LDL is

cleared by the liver for synthesis of bile acids, which are important for emulsifying fats in

the digestive tract, and represent the only avenue for removal of cholesterol from the

body. Apoprotein-B (apo-B) is a major component of LDL, and cellular uptake of LDL

occurs through recognition of apo-B at the receptor binding sites (2).

Dysregulation of LDL function occurs when LDL suffers oxidative damage,

which alters its composition to the extent that it is poorly recognized by hepatocytes.

Conversely, uptake of oxidized LDL is greatly increased in scavenger cells in peripheral

tissues, most notably in macrophages that are situated in the vascular endothelium (2).

For this reason LDL is referred to as ‘bad-cholesterol’, and increased levels are a major

risk factor for cardiovascular disease. (3) However it is probably more appropriate to

refer to oxidized LDL as the bad cholesterol. Mechanisms involved in oxidation of LDL,

and the pathogenesis that ensues from macrophage uptake, are discussed below. Without

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further mention, this should highlight the role of antioxidants in foods as cardiovascular

protective agents.

HDL is synthesized in the liver and is primarily composed of apoprotein-a-1 (apo-

a1) (2). Synthesis of apo-a1 is largely regulated by PPARα, and thus exogenous activators

of PPARα can directly contribute to increases in apo-a1 levels and consequently

increased HDL levels (4). HDL is responsible for reverse transport of cholesterol from

the periphery to the liver for elimination. This process of reverse transport is primarily

mediated by apo-A1 stimulation of lecithin-cholesterol-acetyl-transferase (LCAT), which

esterifies free cholesterol in the periphery for removal by HDL. It also follows that apo-

A1 stimulates ATP-binding cassette transporter A-1 (ABCA1), which is a transporter

protein that enables this exchange of lipids from foam cells to HDL(2). Because of this

mechanism, HDL is referred to as ‘good cholesterol’ and decreased levels represent a risk

factor for cardiovascular disease. Increasing HDL levels is an important drug target and

often occurs through degradation of VLDL, as mentioned above.

Atherosclerosis Pathogenesis

Atherosclerosis essentially involves the inappropriate deposition of soft lipid-

based masses, or atheromas, into the walls of the arterial lumen. These lipids are

primarily derived from circulating LDL. Atheromas start as fatty streaks and then

progress to plaques, which are characterized by accumulation of foam cells (macrophages

that are filled with lipids), proliferation of smooth muscle cells, and increased deposition

of collagen and other debris that progressively narrow and ultimately occlude the artery

(1). Consequences of this narrowing include impaired capacity to respond to vasodilators

such as nitric oxide, diminished nutrient supply to associated tissues; and the preparation

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of an environment for circulating blood clots to lodge thus causing acute ischemic events.

Finally, destabilized plaque can rupture, which initiates a clotting cascade that can

suddenly and completely occlude the artery (3).

Chronic mild vascular inflammation is an independent risk factor for

cardiovascular events. Cytokines (immune signaling chemicals) activate pro-

inflammatory genes and vascular cell adhesion molecules (VCAMs), which allow

neutrophils to adhere to vascular walls and exert their inflammatory activity thus

furthering the local atherogenesis (5). Cytokine release from macrophages may be

induced by transcriptional activators released by oxidized LDL (2), however in the obese

state adipose tissue also releases proinflammatory compounds (7). Mechanisms for

reducing inflammation via diet, exercise, and drug therapy will also be explored in later

sections and is a major feature of cardioprotective therapy mediated through non-lipid

pathways.

Atherosclerosis, particularly in the coronary and cerebral arteries, is a silent killer

because no pain or prior symptoms need be necessary for a lethal event to occur as a

result. Indeed, over 50% of sudden death from cardiovascular disease occurs in

individuals with no previously recognized symptoms, and an artery can be over 70%

obstructed before symptoms (such as angina) develop. Alarmingly, although most

cardiovascular events are suffered in adulthood, atherosclerosis starts in childhood and

progresses throughout life. Autopsies performed on children and adolescents reveal

formation of fatty streak as early as 3 years of age, and adolescents with arterial

obstruction so significant that they could have suffered myocardial infarction (3). Based

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on this information the importance of regular preventative measures achieved through

exercise and diet cannot be overemphasized.

Effects of Exercise

Regular physical activity can profoundly reduce cardiovascular risk through

altering the dynamics of lipoprotein metabolism. This is best explained by summarizing

the mechanisms through which type two diabetes and metabolic syndrome (a complex

characterized by insulin resistance, obesity, hypertension, and dyslipidemia) can

profoundly increase cardiovascular risks, because these conditions are associated with a

sedentary lifestyle. Not all people with cardiovascular disease have diabetes, however, it

is estimated by the American Heart Association that around 50 million people in the

United States have metabolic syndrome (6), while 65 million people in the US suffer

from some sort of cardiovascular disease (3). The discussion that follows will highlight

this close correlation.

Type 2 diabetes and metabolic syndrome are both characterized by insulin

resistance. Insulin is essential for the cellular uptake of dietary fat, protein, and glucose

following a meal (during the post-prandial state) (3). This is important not only for the

effective storage and utilization of nutrients for tissue synthesis and cellular energy, but

for the often overlooked protection against the pathogenic consequences of pronounced

and prolonged increases in blood glucose levels becomes toxic to tissues. The interaction

of glucose with tissues and circulating compounds leads to the formation of advanced

glycated end-product (AGE) complexes, which disrupt normal tissue function in a broad

variety of ways. For our purposes, the glycation of circulating LDL renders it far more

susceptible to oxidative damage, thus increasing its deposition into vascular endothelium.

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Additionally, gylcation of HDL may inhibit its ability for reverse transport of cholesterol

(2).

AGE complex formation is greatly accelerated in a hyperglycemic environment,

which is a hallmark of insulin resistance. Under normal responsiveness to insulin,

glucose uptake is dramatically increased in skeletal muscle and hepatic tissue, which

stabilizes blood glucose levels following a post-prandial spike. This occurs through the

translocation of GLUT-4 receptors to the surface of these cells, which facilitate the

diffusion of glucose into the cytoplasm. Regular exercise favorably enhances this

mechanism, resulting in increased sensitivity to insulin, increased number and

translocation of GLUT-4, and increased glycogen synthase activity (3). Therefore regular

exercise profoundly reduces post-prandial hyperglycemia and consequently reduces

excessive glycation of LDL and HDL. On the other side of the equation, a sedentary

lifestyle results in an insulin resistant state, in which post-prandial blood glucose levels

are slow to stabilize and remain high post-absorptively, and thus LDL and HDL are

excessively glycated.

Fat metabolism is heavily dictated by insulin activity as well as through

adaptations to exercise. LPL activity is regulated by insulin in order to rapidly clear post-

prandial triglycerides: insulin stimulates LPL to liberate free fatty acids (FFA’s) from

VLDL for uptake into adipose tissue for storage. As fat reserves increase, adipose tissue

releases factors that promote insulin resistance (7). In the insulin resistant state,

circulating triglycerides increase and glycogen reserves are diminished due to

insufficient uptake by in skeletal muscle and hepatic tissue. As a consequence highly

metabolically active tissues in the central nervous system and cardiac muscle must rely

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more on FFA’s and ketone bodies as a fuel (3). FFA flux to the liver signals the liver to

increase output of apo-B (and thus increased LDL formation). This combined with

reduced LPL activity leads to significant increases in VLDL and LDL (2).

These trends and vicious cycles are reversible through regular exercise. As

already mentioned, skeletal muscle increases its sensitivity to insulin thus improving

post-prandial glucose clearance. Trained muscle also increases its LPL activity thus

reducing VLDL levels. A major training response is improved utilization of FFA’s as an

energy source at higher levels of intensity. Recent studies suggest that this effect is likely

mediated via PPARδ activation in skeletal muscle. This results in increased LPL activity

and improved mitochondrial populations, which is accompanied by enhanced oxidation

of fatty acids as mediated by upregulation of carnitine palmitoyl transferase activity

(CPT1) – a protein responsible for the transport of fatty acids across mitochondrial

membranes. Because these mechanisms ultimately lead to increases HDL levels, PPARδ

agonist drugs mimic favorable exercise-induced alterations in lipid metabolism (8).

FFA utilization increases in proportion to exercise intensity as intensity

approaches 50% of Vo2 max, and then FFA utilization declines as higher intensities are

achieved (7). Thus exercise at this moderate intensity level is desirable. However higher

intensity resistance training-induced increases in muscle mass also confer benefits in

metabolic syndrome via separate mechanisms not discussed.

Reduction of fat stores in adipose tissue through negative energy balance achieved

through regular exercise leads to decreased output of proinflammatory compounds such

as resistin and interleukin-6. The level of secretion stands in direct relationship to fat

reserves such that decreased reserves also decrease proinflammatory output (7). This is

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crucially important because, as discussed above, inflammation is a prominent risk factor

for cardiovascular events.

Effects of Diet

The ultimate goal of lifestyle and pharmacological interventions is to increase

hepatic clearance of cholesterol from the general circulation. However, once this has

been accomplished, cholesterol must still be eliminated, which is problematic because

cholesterol cannot be degraded in the body. Elimination occurs through hepatic

conversion of cholesterol to bile acids, which are delivered to the gallbladder and

ultimately secreted into the small intestine to assist in the emulsification of fats.

However, most bile acids are reabsorbed at the ileum of the small intestine and returned

to the liver – a process known as enterohepatic cycling. In fact, bile acids may be

recycled up to 18 times before they are finally eliminated in the feces(1).

Bile-acid binding resins are a major class of lipid-lowering drugs that work well

in combination with other interventions because they bind with bile-acids in the small

intestine and increase their elimination in the feces. Consequently the liver must

upregulate LDL receptors in order to pull more cholesterol from the circulation in order

to maintain bile-acid levels (9). Clearance is enabled through upregulation of cholesterol

7 alpha-hydroxylase, which is the rate limiting enzyme in bile-acid synthesis, and this

mechanism is a prominent indirect effect of these drugs (10).

A similar mechanism has been demonstrated for dietary fiber, such that dietary

fiber (particularly soluble fibers – lignans, gums, pectins, etc.) can prevent the

reabsorption of bile-acids and therefore also result in increased LDL clearance and

cholesterol 7 alpha-hydroxylase activity. Additionally, the binding of nutrients such as

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starches and sugars in the small intestine by dietary fibers slows their absorption thus

mitigating post-prandial spikes in blood glucose levels (11).

Reductions in dietary cholesterol and saturated fat intake are generally recognized

preventative dietary strategies for reducing the risk of heart disease. However,

supplementation with certain omega-3 fatty acids may confer much more specific

benefits. Most clinical evidence suggests that these effects are specifically derived from

two omega-3 fatty acids found in fish oils – eicosapentanoic acid (EPA) and

docosahexanoic acid (DHA) - and not necessarily from vegetable sources of omega-3’s

(although more research is necessary regarding potential benefits of vegetable omega-

3’s). The primary mechanism of action involves gradual displacement of arachidonic

acid from phospholipid membranes by DHA and EPA. As a consequence, eicosanoids

become increasingly derived from these fatty acids instead of from arachidonic acid. A 3-

series of prostanoids and thromboxanes are derived from EPA and DHA as opposed to the

2-series derived from arachidonic acid, and as a general trend these 3-series derivatives

tend to have a far less pronounced vasoconstricting and platelet-aggregating effect of the

2-series derived from arachidonic acid because they are much less active at receptor sites

(12).

Inflammatory pathways are also altered as EPA/DHA yield a 5-series of

leukotrienes that competitively inhibit AA-derived 4-series leukotrienes at their binding

sites, thus producing an anti-inflammatory and anti-allergenic effect. EPA and DHA may

also operate as ligands for PPARα, thus promoting increased levels of apo-A1, decreased

levels of apo-B, and increasing LPL activity. Activation of PPARα may also inhibit

smooth muscle proliferation, which is a feature of the pathogenesis atherosclerotic

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plaques. Adverse effects of omega-3 fat supplementation include increased bleeding due

to an anti-aggregating effect and the potential for increased oxidation of LDL as they are

polyunsaturated fats and thus highly prone to oxidative damage (12).

Part 2: PPAR Active Drugs

Peroxisome proliferator activated receptors are transcriptional activators

distributed throughout a diversity of tissues that operate together to produce orchestrated

effects that regulate lipid and energy metabolism. Three major subunits have been

identified: alpha, gamma, and delta – the former two have been exploited by marketed

pharmaceuticals, while drugs that operate on PPARδ are still in the advanced phases of

development. PPARγ coactivator-1-alpha (PGC1-A) is also of interest as it is activated

by nitric oxide and mediates exercise-induced proliferation of mitochondria in skeletal

muscle(13).

PPARα and Fibric Acid Derivatives

The class of lipid lowering drugs known as fibric acid derivatives (FAD’s), or

fibrates, are activating ligands for PPARα. Activation results in increased expression of

LPL in multiple tissue and consequently decreases circulating VLDL. Accompanying this

mechanism is a moderate increase in circulating HDL, both through stabilization of HDL

by VLDL hydrolysis, and increased hepatic expression of apo-A1 which improves

reverse transport of cholesterol. Improved LPL activity with FAD’s may occur via

reduction in the levels of apoliprotein C-III (apo-CIII), which is a component of VLDL’s

and has been demonstrated to inhibit the activity of LPL (2).

Similar to the statin drugs, FAD’s have non-lipid benefits for prevention of

cardiovascular disease. PPARα expression in vascular endothelial cells regulates

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inflammatory processes through complex mechanisms that suppress proinflammatory

pathways, vasoconstriction, and platelet aggregation (5).

Gemfibrozil has two approved clinical uses in the US: 1) the treatment of patients

with high triglyceride levels who are at increased risk for developing pancreatitis and 2)

patients with high serum triglycerides and low HDL levels. FAD’s should not be the first

line of defense for patients with hypercholesterolemia but low serum triglycerides.

FAD’s are an excellent combination drug, either with statin drugs or bile-acid binding

resins (11)

PPARgamma and Thiazolidinediones

The class of lipid lowering and anti-diabetic drugs known as thiazolidinediones or

glitazones are activators of PPARγ. In adipose and muscle tissue, this effect appears to

increase the output of LPL and thus improves insulin sensitivity and post-prandial

clearance of glucose and triglycerides. GLUT-4 transporter activity in adipocytes is also

enhanced. Additionally, PPARγ activation may lead to favorable redistribution of fat

stores from visceral adipose tissue to subcutaneous adipose tissue (14).

Similar to FAD’s and statins, glitazones also provide non-lipid benefits through

suppression of proinflammatory signaling pathways, mediated through their activity at

PPARγ binding sites in vascular endothelial cells and macrophages. Specifically PPARγ

expression in macrophages and endothelial cells increases the efflux of cholesterol for

reverse transport via HDL (4). Major side effects primarily concern increased plasma

volume and consequently an increased risk for hospitalization due to congestive heart

failure (14).

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 Currently in the developmental phases is a drug referred to as propionic acid

derivative 8 (compound 8). Compound 8 has both PPARα and PPARγ activity, and is thus

a promising drug for reducing atherosclerosis and dyslipidemia in patients with type 2

diabetes mellitus (4).

PPARδ and GW501516

In contrast to PPARα and PPARγ activators, PPARδ activating drugs are still in

the developmental stages. GlaxoSmithKline is developing a drug currently referred to as

GW501516, which is in phase II of development. GW501516 shows promise for treating

hyperlipidemia through a variety of mechanisms.

Dramatic increases in HDL levels have been observed in human and primate

studies with GW501516 (4, 8). This effect is primarily achieved through increased

hydrolysis of VLDL that ultimately occurs through upregulation in oxidative activity of

skeletal muscle mitochondria such that FFA utilization as a fuel is enhanced. Additional

lipid associated benefits include increased expression of apo-1A and ATP-binding

cassette transporter A-1 (ABCA1). ABCA1 is a protein that enables the exchange of

lipids from foam cells to HDL. Thus HDL levels and efficacy are increased by

GW501516 (8).

Activation of PPARδ may also provide important cardioprotection with specific

regard to reperfusion-induced oxidative stress. As blood flow is returned to ischemic

tissue, oxidative stress and inflammation can occur to the extent that they are more

damaging than the actual ischemia. PPARδ mediated protection occurs through

upregulation in antioxidant mechanisms and inhibition of cardiac myocyte apoptosis

triggered by oxidative stress (15). Additionally, GW501516 may inhibit cardiac fibrosis

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through the inhibition of cardiac fibroblast collagen synthesis and fibroblast proliferation.

Thus, this drug has a potential role in the treatment and prevention of congestive heart

failure (16).

Possible adverse effect for GW501516 involves its role as an angiogenic agent.

Excessive angiogenesis is associated with increased inflammatory activity and tumor

growth. In contrast to PPARα and PPARγ, which appear to be anti-angionenic through

their impact on eicosanoid activity, PPARδ stimulates vascular endothelial growth factor

(VEGF), which suggests that patients at risk for angiogenesis be increasingly monitered

if taking PPARδ’s such as GW501516. However, GW501516 may also represent a novel

and inadvertent pharmacological agent for promoting wound healing and treating

ischemic heart disease precisely due to its angiogenic properties (17).

Conclusions

Exciting new lines of therapy are emerging for the treatment of dyslipidemia, and

appear to operate through similar mechanisms and receptor activity. It is likely that as

advances are made in exercise physiology to understand the role of these receptors in

favorable adaptations to physical activity, increasingly precise and effective

pharmacological agents can be developed. It has also been demonstrated that

combination of exercise and diet produces a broader range of benefit that are generally

more potent and without side-effect. This justifies the generally accepted protocol of diet

and exercise as the first line of treatment in hyperlipidemic individuals, and

pharmacological intervention only if lipid levels fail to respond to these lifestyle changes.

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