Brian N. Finck

Giulia Chinetti

Bart Staels

PPARs/RXRs in Cardiovascular Physiology and Disease

The peroxisome proliferator-activated receptors (PPARs) consist of three related transcription factors that serve to regulate a number of cellular processes that are central to cardiovascular health and disease.  Numerous pharmacologic studies have assessed the effects of specific PPAR agonists in clinical trials and have provided insight into the clinical effects of these genes while genetic studies have demonstrated clinical associations between PPAR polymorphisms and abnormal cardiovascular phenotypes.  With the abundance of data available from these studies as a background, PPAR pharmacogenetics has  become a promising and rapidly advancing field.  This review focuses on summarizing the current state of understanding of PPAR genetics and pharmacogenetics and the important implications for the individualization of therapy for patients with cardiovascular diseases.

Sharon Cresci

PPAR Genomics and Pharmacogenomics:  Implications for Cardiovascular Disease

Trials of peroxisome proliferator-activated receptor (PPAR) agonists have shown mixed results for cardiovascular prevention.  Fibrates are PPAR-<svg style="vertical-align:-0.1254pt;width:8.9375px;" id="M1" height="7.1750002" version="1.1" viewBox="0 0 8.9375 7.1750002" width="8.9375"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,7.175)">
		<g transform="translate(72,-66.26)">
			<text transform="matrix(1,0,0,-1,-71.95,66.44)">
				<tspan style="font-size: 12.50px; " x="0" y="0">𝛼</tspan>
			</text>

		</g>
	</g>
</svg> agonists that act primarily to improve dyslipidemia. Based on low- and high-density 
    lipoprotein cholesterol (LDL and HDL) effects, gemfibrozil may be of greater cardiovascular benefit than expected, fenofibrate performed about as expected, and bezafibrate performed worse than expected.  Increases in both cardiovascular and noncardiovascular serious adverse events have been observed with some fibrates.  Thiazolidinediones (TZDs) are PPAR-<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M2" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,9.9375)">
		<g transform="translate(72,-64.05)">
			<text transform="matrix(1,0,0,-1,-71.95,66.44)">
				<tspan style="font-size: 12.50px; " x="0" y="0">𝛾</tspan>
			</text>

		</g>
	</g>
</svg> agonists used to improve impaired glucose metabolism but also influence lipids.  
    Pioglitazone reduces atherosclerotic events in diabetic subjects, but has no net cardiovascular benefit due to increased congestive heart failure risk.  Rosiglitazone may increase the risk of atherosclerotic events, and has a net harmful effect on the cardiovascular system when congestive heart failure is included.  The primary benefit of TZDs appears to be the prevention of diabetic microvascular complications. Dual PPAR-<svg style="vertical-align:-2.34499pt;width:21.225px;" id="M3" height="13.6125" version="1.1" viewBox="0 0 21.225 13.6125" width="21.225"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,13.6125)">
		<g transform="translate(72,-61.11)">
			<text transform="matrix(1,0,0,-1,-71.95,63.5)">
				<tspan style="font-size: 12.50px; " x="0" y="0">𝛼</tspan>
				<tspan style="font-size: 12.50px; " x="7.0391889" y="0">/</tspan>
				<tspan style="font-size: 12.50px; " x="10.515023" y="0">𝛾</tspan>
			</text>

		</g>
	</g>
</svg> agonists have had unacceptable adverse effects but more selective agents are in development. PPAR-<svg style="vertical-align:-0.13794pt;width:7.9875002px;" id="M4" height="10.7375" version="1.1" viewBox="0 0 7.9875002 10.7375" width="7.9875002"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,10.7375)">
		<g transform="translate(72,-63.41)">
			<text transform="matrix(1,0,0,-1,-71.95,63.6)">
				<tspan style="font-size: 12.50px; " x="0" y="0">𝛿</tspan>
			</text>

		</g>
	</g>
</svg> and pan-agonists are also in development.  It will be imperative to prove that future PPAR agonists not only prevent atherosclerotic events but also result in a net reduction on total cardiovascular events without significant noncardiovascular adverse effects with long-term use.

Jennifer G. Robinson

Should We Use PPAR Agonists to Reduce Cardiovascular Risk?

Gene expression data obtained in mouse heart indicate that increased expression for the nuclear receptor, peroxisomal proliferator activated receptor <svg     style="vertical-align:-0.1638pt;width:9.7749996px;" id="M2" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FC"/></g>

		
	
</svg> (PPAR<svg     style="vertical-align:-0.1638pt;width:9.7749996px;" id="M3" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FC"/></g>

		
	
</svg>), prompts the postnatal transition from predominantly carbohydrate to fatty acid oxidation preference. However, no phenotypic or proteomic data are available to confirm downstream signaling and metabolic transition in mice. We studied the hypothesis that shifts in nuclear receptor expression trigger the newborn metabolic switch in a newborn sheep. This species is well characterized with regards to developmental changes in substrate oxidative metabolism. Heart tissues from fetal (130 days
gestation), newborn <svg     style="vertical-align:-0.546pt;width:14.825px;" id="M4" height="10.15" version="1.1" viewBox="0 0 14.825 10.15" width="14.825"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,9.413)"><path id="x2264" d="M531 71l-474 214v50l474 215v-56l-416 -184l416 -183v-56zM531 -40h-474v50h474v-50z" /></g>

		
	
</svg>24 hours, and 30-day old lambs were evaluated for protein expression from multiple enzymes controlling oxidative metabolism as well as principal nuclear receptors and coactivators. Although muscle and liver type carnitine palmitoyl transferases I showed no significant changes to correspond to the metabolic transition, hexokinase II protein content
showed a profound transient drop, and pyruvate dehydrogenase kinase steadily increased. PPAR<svg     style="vertical-align:-0.1638pt;width:9.7749996px;" id="M5" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FC"/></g>

		
	
</svg> showed no increases preceding or during the transition, while peroxisomal proliferator activated receptor gamma coactivator-1 (PGC-1) increased approximately 20-fold transiently in newborn heart in conjunction with significant increases in thyroid hormone receptor <svg     style="vertical-align:-0.1638pt;width:9.7749996px;" id="M6" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FC"/></g>

		
	
</svg>1 and retinoid-activated receptor <svg     style="vertical-align:-0.1638pt;width:9.7749996px;" id="M7" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FC"/></g>

		
	
</svg>. These data challenge the paradigm that increases in PPAR<svg     style="vertical-align:-0.1638pt;width:9.7749996px;" id="M8" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FC"/></g>

		
	
</svg> prompt the postnatal metabolic switch, and suggest that other nuclear receptors play a major role. As thyroid hormone (TH) modulates PGC-1 expression in sheep during development, these data further suggest that well-characterized perinatal TH surge in sheep contributes to this metabolic switch.

Norman E. Buroker

Xue-Han Ning

Michael Portman

Cardiac PPAR<svg style="vertical-align:-0.1638pt" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path id="x1D6FC" d="M545 106q-67 -118 -134 -118q-24 0 -40 37.5t-30 129.5h-2q-47 -72 -103 -119.5t-108 -47.5q-47 0 -76 45.5t-29 119.5q0 113 85 204t174 91q47 0 70 -33.5t43 -119.5h3q32 47 80 140l55 13l10 -9q-47 -80 -138 -201q17 -99 27.5 -136t22.5 -37q23 0 69 61zM333 204q-14 98 -31 149.5t-50 51.5q-49 0 -94 -70t-45 -164q0 -55 15.5 -86t40.5 -31q70 0 164 150z"/></g></svg> Protein Expression is Constant as Alternate Nuclear Receptors and PGC-1 Coordinately Increase During the Postnatal Metabolic Transition

Investigating the metabolic functions of the nuclear receptor peroxisome proliferator-activated receptor <svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M2" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
    <g transform="matrix(1.25,0,0,-1.25,0,9.9375)">
        <g transform="translate(72,-64.05)">
            <text transform="matrix(1,0,0,-1,-71.95,66.44)">
                <tspan style="font-size: 12.50px; " x="0" y="0">𝛾</tspan>
            </text>

        </g>
    </g>
</svg> (PPAR<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M3" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
    <g transform="matrix(1.25,0,0,-1.25,0,9.9375)">
        <g transform="translate(72,-64.05)">
            <text transform="matrix(1,0,0,-1,-71.95,66.44)">
                <tspan style="font-size: 12.50px; " x="0" y="0">𝛾</tspan>
            </text>

        </g>
    </g>
</svg>) has been extremely rewarding over the past years. 
Uncovering the biologic roles of PPAR<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M4" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
    <g transform="matrix(1.25,0,0,-1.25,0,9.9375)">
        <g transform="translate(72,-64.05)">
            <text transform="matrix(1,0,0,-1,-71.95,66.44)">
                <tspan style="font-size: 12.50px; " x="0" y="0">𝛾</tspan>
            </text>

        </g>
    </g>
</svg> and its mechanism of action has greatly advanced our understanding of the transcriptional control of lipid and glucose metabolism, and compounds such as thiazolidinediones which directly regulate PPAR<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M5" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
    <g transform="matrix(1.25,0,0,-1.25,0,9.9375)">
        <g transform="translate(72,-64.05)">
            <text transform="matrix(1,0,0,-1,-71.95,66.44)">
                <tspan style="font-size: 12.50px; " x="0" y="0">𝛾</tspan>
            </text>

        </g>
    </g>
</svg> have proven to exhibit potent insulin-sensitizer effects in the treatment of diabetes. We review here recent advances on the emerging role of growth hormone releasing peptides in regulating PPAR<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M6" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
    <g transform="matrix(1.25,0,0,-1.25,0,9.9375)">
        <g transform="translate(72,-64.05)">
            <text transform="matrix(1,0,0,-1,-71.95,66.44)">
                <tspan style="font-size: 12.50px; " x="0" y="0">𝛾</tspan>
            </text>

        </g>
    </g>
</svg> through interaction with scavenger receptor CD36 and ghrelin GHS-R1a receptor. With the impact that these peptides exert on the metabolic pathways involved in lipid metabolism and energy homeostasis, it is hoped that the development of novel approaches in the regulation of PPAR functions will bring additional therapeutic possibilities to face problems related to metabolic diseases.

Annie Demers

Am&#xE9;lie Rodrigue-Way

Andr&#xE9; Tremblay

Hexarelin Signaling to PPAR<svg style="vertical-align:-3.56265pt" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path id="x1D6FE" d="M478 372q0 -39 -31 -97t-61 -98t-78 -98q-45 -55 -73 -102q-13 -79 -13 -197q-11 -11 -43.5 -25.5t-53.5 -15.5l-15 17q5 35 26 101.5t47 123.5q8 72 -1.5 174.5t-37.5 178.5q-14 37 -29 37q-20 0 -67 -65l-25 21q37 60 73 90.5t63 30.5q47 0 72 -112q13 -56 17.5 -141.5&#xA;t0.5 -143.5h2q155 193 155 297q0 26 -12 47q-5 8 -5 15q0 16 12.5 27t29.5 11q21 0 34 -21t13 -55z" /></g></svg> in Metabolic Diseases

Peroxisome proliferators activated receptors (PPARs) are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostasis. To the extent that PPAR agonists improve diabetic dyslipidaemia and insulin resistance, these agents have been considered to reduce cardiovascular risk. However, data from murine models suggests that PPAR agonists also have independent anti-atherosclerotic actions, including the suppression of vascular inflammation, oxidative stress, and activation of the renin angiotensin system. Many of these potentially anti-atherosclerotic effects are thought to be mediated by transrepression of nuclear factor-kB, STAT, and activator protein-1 dependent pathways. In recent clinical trials, PPAR<svg style="vertical-align:-0.1254pt;width:8.9375px;" id="M1" height="7.1750002" version="1.1" viewBox="0 0 8.9375 7.1750002" width="8.9375"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,7.175)">
		<g transform="translate(72,-66.26)">
			<text transform="matrix(1,0,0,-1,-71.95,66.44)">
				<tspan style="font-size: 12.50px; " x="0" y="0">𝛼</tspan>
			</text>

		</g>
	</g>
</svg> agonists have been shown to be effective in the primary prevention of cardiovascular events, while their cardiovascular benefit in patients with established cardiovascular disease remains equivocal. However, the use of 
PPAR<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M2" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,9.9375)">
		<g transform="translate(72,-64.05)">
			<text transform="matrix(1,0,0,-1,-71.95,66.44)">
				<tspan style="font-size: 12.50px; " x="0" y="0">𝛾</tspan>
			</text>

		</g>
	</g>
</svg> agonists, and more recently dual PPAR<svg style="vertical-align:-0.1254pt;width:8.9375px;" id="M3" height="7.1750002" version="1.1" viewBox="0 0 8.9375 7.1750002" width="8.9375"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,7.175)">
		<g transform="translate(72,-66.26)">
			<text transform="matrix(1,0,0,-1,-71.95,66.44)">
				<tspan style="font-size: 12.50px; " x="0" y="0">𝛼</tspan>
			</text>

		</g>
	</g>
</svg>/<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M4" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,9.9375)">
		<g transform="translate(72,-64.05)">
			<text transform="matrix(1,0,0,-1,-71.95,66.44)">
				<tspan style="font-size: 12.50px; " x="0" y="0">𝛾</tspan>
			</text>

		</g>
	</g>
</svg> coagonists, has been associated with an excess in cardiovascular events, 
possibly reflecting unrecognised fluid retention with potent agonists of the 
PPAR<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M5" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,9.9375)">
		<g transform="translate(72,-64.05)">
			<text transform="matrix(1,0,0,-1,-71.95,66.44)">
				<tspan style="font-size: 12.50px; " x="0" y="0">𝛾</tspan>
			</text>

		</g>
	</g>
</svg> receptor. Newer pan agonists, which retain their anti-atherosclerotic activity without weight gain, may provide one solution to this problem. However, the complex biologic effects of the PPARs may mean that only vascular targeted agents or pure transrepressors will realise the goal of preventing atherosclerotic vascular disease.

Anna C. Calkin

Merlin C. Thomas

PPAR Agonists and Cardiovascular Disease in Diabetes

Historically, platelets were viewed as simple anucleate cells responsible for initiating thrombosis and maintaining
hemostasis, but clearly they are also key mediators of inflammation and immune cell activation. An emerging body of
evidence links platelet function and thrombosis to vascular inflammation.  peroxisome proliferator-activated receptors
(PPARs) play a major role in modulating inflammation and, interestingly, PPARs (PPAR<svg style="vertical-align:-2.29482pt;width:8.8500004px;" id="M1" height="13.425" version="1.1" viewBox="0 0 8.8500004 13.425" width="8.8500004"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,13.425)">
		<g transform="translate(72,-61.26)">
			<text transform="matrix(1,0,0,-1,-71.95,63.6)">
				<tspan style="font-size: 12.50px; " x="0" y="0">𝛽</tspan>
			</text>

		</g>
	</g>
</svg>/<svg style="vertical-align:-0.13794pt;width:7.9875002px;" id="M2" height="10.7375" version="1.1" viewBox="0 0 7.9875002 10.7375" width="7.9875002"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,10.7375)">
		<g transform="translate(72,-63.41)">
			<text transform="matrix(1,0,0,-1,-71.95,63.6)">
				<tspan style="font-size: 12.50px; " x="0" y="0">𝛿</tspan>
			</text>

		</g>
	</g>
</svg> and PPAR<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M3" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,9.9375)">
		<g transform="translate(72,-64.05)">
			<text transform="matrix(1,0,0,-1,-71.95,66.44)">
				<tspan style="font-size: 12.50px; " x="0" y="0">𝛾</tspan>
			</text>

		</g>
	</g>
</svg>) were recently
identified in platelets.  Additionally, PPAR agonists attenuate platelet activation; an important discovery for two reasons.
First, activated platelets are formidable antagonists that initiate and prolong a cascade of events that contribute to
cardiovascular disease (CVD) progression.  Dampening platelet release of proinflammatory mediators, including
CD40 ligand (CD40L, CD154), is essential to hinder this cascade.  Second, understanding the biologic importance
of platelet PPARs and the mechanism(s) by which PPARs regulate platelet activation will be imperative in designing
therapeutic strategies lacking the deleterious or unwanted side effects of current treatment options.

S. L. Spinelli

J. J. O'Brien

S. Bancos

G. M. Lehmann

D. L. Springer

N. Blumberg

C. W. Francis

M. B. Taubman

R. P. Phipps

The PPAR-Platelet Connection: Modulators of Inflammation and Potential Cardiovascular Effects

Proliferation of vascular smooth muscle cells (SMCs) is a critical process for the development of atherosclerosis and complications of procedures used to treat atherosclerotic diseases, including postangioplasty restenosis, vein graft failure, and transplant vasculopathy. Peroxisome proliferator-activated receptor (PPAR) <svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M2" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
    
        
            <g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FE"/></g>

        
    
</svg> is a member of the nuclear hormone receptor superfamily and the molecular target for the thiazolidinediones (TZD), used clinically to treat insulin resistance in patients with type 2 diabetes. In addition to their efficacy to improve insulin sensitivity, TZD exert a broad spectrum of pleiotropic beneficial effects on vascular gene expression programs. In SMCs, PPAR<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M3" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
    
        
            <g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FE"/></g>

        
    
</svg> is prominently upregulated during neointima formation and suppresses the proliferative response to injury of the arterial wall. Among the molecular target genes regulated by PPAR<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M4" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
    
        
            <g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FE"/></g>

        
    
</svg> in SMCs are genes encoding proteins involved in the regulation of cell-cycle progression, cellular senescence, and apoptosis. This inhibition of SMC proliferation is likely to contribute to the prevention of atherosclerosis and postangioplasty restenosis observed in animal models and proof-of-concept clinical studies. This review will summarize the transcriptional target genes regulated by PPAR<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M5" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
    
        
            <g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FE"/></g>

        
    
</svg> in SMCs and outline the therapeutic implications of PPAR<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M6" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
    
        
            <g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FE"/></g>

        
    
</svg> activation for the treatment and prevention of atherosclerosis and its complications.

Florence Gizard

Dennis Bruemmer

Transcriptional Control of Vascular Smooth Muscle Cell Proliferation by Peroxisome Proliferator-Activated Receptor-<svg style="vertical-align:-3.56265pt" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path id="x1D6FE" d="M478 372q0 -39 -31 -97t-61 -98t-78 -98q-45 -55 -73 -102q-13 -79 -13 -197q-11 -11 -43.5 -25.5t-53.5 -15.5l-15 17q5 35 26 101.5t47 123.5q8 72 -1.5 174.5t-37.5 178.5q-14 37 -29 37q-20 0 -67 -65l-25 21q37 60 73 90.5t63 30.5q47 0 72 -112q13 -56 17.5 -141.5t0.5 -143.5h2q155 193 155 297q0 26 -12 47q-5 8 -5 15q0 16 12.5 27t29.5 11q21 0 34 -21t13 -55z"/></g></svg>: Therapeutic Implications for Cardiovascular Diseases

Peroxisome proliferator-activated receptor-<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M2" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FE"/></g>

		
	
</svg>  (PPAR-<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M3" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FE"/></g>

		
	
</svg>), an essential transcriptional mediator of adipogenesis, lipid metabolism, insulin sensitivity, and glucose homeostasis, is increasingly recognized as a key player in inflammatory cells and in cardiovascular diseases (CVD) such as hypertension, cardiac hypertrophy, congestive heart failure, and atherosclerosis. PPAR-<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M4" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FE"/></g>

		
	
</svg> agonists, the thiazolidinediones (TZDs), increase insulin sensitivity, lower blood glucose, decrease circulating free fatty acids and triglycerides, lower blood pressure, reduce inflammatory markers, and reduce atherosclerosis in insulin-resistant patients and animal models. Human genetic studies on PPAR-<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M5" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FE"/></g>

		
	
</svg> have revealed that functional changes in this nuclear receptor are associated with CVD. Recent controversial clinical studies raise the question of deleterious action of PPAR-<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M6" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FE"/></g>

		
	
</svg> agonists on the cardiovascular system. These complex interactions of metabolic responsive factors and cardiovascular disease promise to be important areas of focus for the future.

Sheng Zhong Duan

Christine Y. Ivashchenko

Michael G. Usher

Richard M. Mortensen

PPAR-<svg style="vertical-align:-3.56265pt" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path id="x1D6FE" d="M478 372q0 -39 -31 -97t-61 -98t-78 -98q-45 -55 -73 -102q-13 -79 -13 -197q-11 -11 -43.5 -25.5t-53.5 -15.5l-15 17q5 35 26 101.5t47 123.5q8 72 -1.5 174.5t-37.5 178.5q-14 37 -29 37q-20 0 -67 -65l-25 21q37 60 73 90.5t63 30.5q47 0 72 -112q13 -56 17.5 -141.5t0.5 -143.5h2q155 193 155 297q0 26 -12 47q-5 8 -5 15q0 16 12.5 27t29.5 11q21 0 34 -21t13 -55z"/></g></svg> in the Cardiovascular System

The primary aim of this study was to examine prospectively the associations between 5 peroxisome proliferator-activated receptor (<i>PPAR</i>) single nucleotide polymorphisms (SNPs) and cardiovascular morbidity and mortality in a community-based cohort study in Washington County, Maryland.   Data were analyzed from 9,364 Caucasian men and women participating in CLUE-II.  Genotyping on 5 <i>PPAR</i> polymorphisms was conducted using peripheral DNA samples collected in 1989. The followup period was from 1989 to 2003.  The results showed that there were no statistically significant associations between the <i>PPAR</i> SNPs and cardiovascular deaths or events. In contrast, statistically significant age-adjusted associations were observed for PPARG rs4684847 with both baseline body mass and blood pressure, and for PPARG rs709158, PPARG rs1175543, and PPARD rs2016520 with baseline cholesterol levels. Future studies should be conducted to confirm these findings and to explore the associations in populations with greater racial and ethnic diversity.

L. Gallicchio

Bindu Kalesan

Han-Yao Huang

Paul Strickland

Sandra C. Hoffman

Kathy J. Helzlsouer

Genetic Polymorphisms of Peroxisome Proliferator-Activated Receptors and the Risk of Cardiovascular Morbidity and Mortality in a Community-Based Cohort in Washington County, Maryland

About this journal

<p><em>PPAR Research</em> publishes articles related to mechanisms involved in the activation of peroxisome proliferator-activated receptors, as well as their role in regulation of cellular differentiation, development, energy homeostasis and metabolic function.</p>


Journal profile

Meet the editorial board

<p>Chief Editor, Dr Xiao-Jie Lu, is dedicated to basic and translational research on liver diseases. His research at Nanjing Medical University, China, focuses&nbsp;on exploring these diseases' underlying mechanisms that may be translatable to novel diagnostic biomarkers or therapeutic targets.</p>


Editor spotlight

Submit your proposal

Do you think there is an emerging area of research that really needs to be highlighted? Or an existing research area that has been overlooked or would benefit from deeper investigation? Raise the profile of a research area by leading a Special Issue.

Special Issues

Author guidelines

Editorial board

Databases and indexing

title

PPAR Research publishes articles related to mechanisms involved in the activation of peroxisome proliferator-activated receptors, as well as their role in regulation of cellular differentiation, development, energy homeostasis and metabolic function.

description

https://images.hindawi.com/journals/ppar/ppar.banner.jpg

twitter:card

twitter:description

twitter:site

twitter:title

twitter:url

twitter:image

PPAR Research | Hindawi

PPAR Research

<p>This Issue is now open for submissions.</p>
<p>Papers are published upon acceptance, regardless of the Special Issue publication date.</p>


PPAR Research

PPARs/RXRs in Cardiovascular Physiology and Disease

PPARs/RXRs in Cardiovascular Physiology and Disease

Articles