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Br J Pharmacol. Aug 2012; 166(7): 1981–1992.
PMCID: PMC3402765

Submaximal PPARγ activation and endothelial dysfunction: new perspectives for the management of cardiovascular disorders

Abstract

PPARγ activation plays an important role in glucose metabolism by enhancing insulin sensitization. PPARγ is a primary target for thiazolidinedione-structured insulin sensitizers like pioglitazone and rosiglitazone employed for the treatment of type 2 diabetes mellitus. Additionally, PPARγ activation inhibits adhesion cascades and detrimental vascular inflammatory events. Importantly, activation of PPARγ plays a distinctive role in regulating the physiology and expression of endothelial nitric oxide synthase (eNOS) in the endothelium, resulting in enhanced generation of vascular nitric oxide. The PPARγ activation-mediated vascular anti-inflammatory and direct endothelial functional regulatory actions could, therefore, be beneficial in improving the vascular function in patients with atherosclerosis and hypertension with or without diabetes mellitus. Despite the disappointing cardiac side effect profile of rosiglitazone-like PPARγ full agonists, the therapeutic potential of novel pharmacological agents targeting PPARγ submaximally cannot be ruled out. This review discusses the potential regulatory role of PPARγ on eNOS expression and activation in improving the function of vascular endothelium. We argue that partial/submaximal activation of PPARγ could be a major target for vascular endothelial functional improvement. Interestingly, newly synthesized partial agonists of PPARγ such as balaglitazone, MBX-102, MK-0533, PAR-1622, PAM-1616, KR-62776 and SPPARγM5 are devoid of or have a reduced tendency to cause the adverse effects associated with full agonists of PPARγ. We propose that the vascular protective properties of pharmacological agents, which submaximally activate PPARγ, should be investigated. Moreover, the therapeutic opportunities of agents that submaximally activate PPARγ in preventing vascular endothelial dysfunction (VED) and VED-associated cardiovascular disorders are discussed.

Keywords: PPARγ partial/submaximal activation, eNOS, EDRF, endothelial function, vascular complications

Introduction

PPARγ, a ligand-activated transcription factor of the nuclear hormone receptor family, regulates gene expression for glucose homeostasis. Activation of PPARγ causes insulin sensitization, and thus favours glucose metabolism (Saltiel and Olefsky, 1996; Bishop-Bailey, 2000; Lebovitz and Banerji, 2001). Subsequently, PPARγ agonists were approved for the treatment of insulin resistance-associated type 2 diabetes mellitus (T2DM) (Lebovitz and Banerji, 2001; Dubois et al., 2002). Thiazolidinediones such as ciglitazone, troglitazone, rosiglitazone and pioglitazone are well-studied full agonists of PPARγ, and among them, pioglitazone is the only available PPARγ agonist used clinically to treat T2DM (Forst et al., 2011). The other thiazolidinedione class of drugs are not used clinically due to their adverse profile (Nesto et al., 2003; Balakumar et al., 2007a,b; Quinn et al., 2008; Patel, 2009), and unfortunately even the use of pioglitazone has recently been restricted to a few countries as the US Food and Drug Administration warned that it may cause urinary bladder cancer. Thiazolidinediones, including rosiglitazone, were withdrawn from the market of several countries due to an increased risk of cardiovascular events (Patel, 2009; Palee et al., 2011). Although the adverse profiles of full agonists of PPARγ are highly disappointing, the unexplored therapeutic potential of novel pharmacological interventions targeting PPARγ submaximally (Table 1), for the prevention of cardiovascular disorders, cannot be ruled out.

Table 1
Pharmacological agents that submaximally activate PPARγ that need special attention to explore their vascular protective potentials

There is accumulating evidence that activation of PPARγ plays an essential role in the regulation of the vascular endothelial function (Polikandriotis et al., 2005; Duan et al., 2008; Yu et al., 2010). The endothelium is an innermost lining of the blood vessel that is anti-coagulant and anti-thrombotic in nature, thus it maintains the free flow of blood through vessels. It releases various mediators involved in the regulation of vascular tone that include NO, known as endothelium-derived relaxing factor. NO is a key regulator of cardiovascular function as it mediates vasorelaxation, inhibits leucocyte–endothelial adhesion and prevents platelet aggregation (Naseem, 2005; Desjardins and Balligand, 2006; Balakumar et al., 2008a; Jindal et al., 2008; Kaur et al., 2010a), the actions of which could be of benefit in averting the pathogenesis of cardiovascular disorders such as atherosclerosis, hypertension and ischaemic heart disease.

NO is synthesized in the endothelium from L-arginine by endothelial NOS (eNOS) (Palmer et al., 1988; Wyatt et al., 2004). Vascular endothelial dysfunction (VED) is specified as an impairment of endothelium-dependent vasorelaxation resulting from eNOS down-regulation or inactivation, and the subsequent reduction in NO levels, leading to deregulation of vascular homeostasis and induction of cardiovascular dysfunction (Rush et al., 2005; Balakumar et al., 2008a,b; Balakumar and Kaur, 2009). In addition, high oxidative stress may account for the development of VED as the superoxide anion radical (O2−.) combines with NO to decrease the bioavailability of endothelial NO. Nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase is known to produce superoxide anion, while superoxide dismutase (SOD) degrades superoxide anion. The overexpression of NADPH oxidase and reduced expression of SOD could therefore cause increased generation of superoxide anion, which could reduce the bioavailability of endothelial NO (Hwang et al., 2005), leading to the development of a dysfunctional endothelium. The VED has been associated with various cardiovascular disorders such as atherosclerosis (Desjardins and Balligand, 2006), hypertension (Puddu et al., 2000) and coronary artery disease (Caramori and Zago, 2000). Therefore, maintaining a normal function of the vascular endothelium by maintaining the normal activation of eNOS and generation of NO in the vascular bed is essential for the prevention of the progression of detrimental cardiovascular disorders. Interestingly, recent studies have demonstrated a key role of PPARγ in regulating the function of the vascular endothelium (Ríos-Vázquez et al., 2006; Duan et al., 2008; Kaur et al., 2010b; Yu et al., 2010). There is evidence that activation of PPARγ causes eNOS activation and NO generation involving diverse mechanisms (Calnek et al., 2003; Cho et al., 2004; Polikandriotis et al., 2005). It is important to identify the signalling system involved in PPARγ-mediated eNOS activation for advancing our current knowledge of the beneficial role of novel PPARγ agonists in preventing the induction and progression of VED. In this review we discuss the potential regulatory role of PPARγ on eNOS expression and activation, and novel therapeutic openings of submaximal (diminished maximal) PPARγ agonists in preventing VED and VED-associated cardiovascular disorders.

Mechanism of eNOS activation

The activation of eNOS for the generation of endothelial NO is regulated by various kinases and phosphatases. Structurally, eNOS consists of two terminal domains, oxygenase-NH2 and reductase-COOH, and it also has a few well-described sites for phosphorylation/dephosphorylation such as Ser1177 and Thr495. Some other sites that regulate eNOS activity, Ser633, Ser114 and Ser615, have also been identified; however, their precise roles remain controversial (Mount et al., 2007). The eNOS has a binding site for calmodulin necessary for the enzyme activity (Mount et al., 2007). The regulation of eNOS expression and activation is influenced by various cellular events such as transcriptional regulation, protein–protein interaction, phosphorylation and dephosphorylation at different amino acid sequences of eNOS (Govers and Rabelink, 2001).

The eNOS is chiefly expressed in the vascular endothelium. Shear stress, induced by flow of fluid across the endothelium, can up-regulate the expression of eNOS (Noris et al., 1995). In addition, various growth factors such as vascular endothelial growth factor, basic fibroblast growth factor and epidermal growth factor up-regulate the expression of eNOS (Kroll and Waltenberger, 1998; Zheng et al., 1999). Moreover, insulin has been shown to play a key role in the up-regulation of eNOS (Kuboki et al., 2000). Interestingly, a low concentration of oxidized low-density lipoprotein (ox-LDL) has been shown to up-regulate eNOS (Hirata et al., 1995). Conversely, a high concentration of ox-LDL down-regulates the expression of eNOS (Laufs et al., 1998). It should be noted that excessive NO itself can reduce eNOS expression through cGMP-mediated activation of a negative feedback regulatory mechanism (Vaziri and Wang, 1999).

The binding of eNOS to caveolin-1 in endothelial cells results in eNOS inactivation (Ju et al., 1997). The protein–protein interaction between eNOS and caveolin-1 markedly reduces eNOS activity because caveolin-1 hampers calmodulin binding to eNOS when cytosolic calcium levels are low (Michel et al., 1997). On the other hand, the interaction of heat shock protein 90 (HSP90) with eNOS results in eNOS activation (Garcia-Cardena et al., 1998). Interestingly, protein–protein interaction between HSP90 and eNOS enhances eNOS activity by inducing calmodulin-stimulated displacement of eNOS from caveolin-1 (Gratton et al., 2000). In addition, HSP90 and eNOS interact to enhance PKB (Akt)-mediated eNOS activation in the endothelium (Fontana et al., 2002; Takahashi and Mendelsohn, 2003).

As summarized in Table 2, the eNOS activity is determined through phosphorylation or dephosphorylation at Ser1177, Ser633 and Thr495 sites of eNOS by multiple protein kinases, including PKB, PKA, PKC, AMP-activated protein kinase (AMPK) and ERK, and phosphatases such as protein phosphatase (PP)1 and PP2A in response to multiple stimuli via shear stress, growth factors, insulin, etc. (Dimmeler et al., 1999; Michell et al., 1999; 2001; Fleming et al., 2001; Mount et al., 2007; Chen et al., 2009; Xiao et al., 2011). Dimmeler et al. (1999) showed that PKB phosphorylates eNOS at the Ser1177 site by a Ca2+-independent regulatory mechanism to activate eNOS. The PKA signalling activates eNOS by enhancing the phosphorylation of Ser1177 and dephosphorylation of Thr495, whereas the PKC signalling in endothelial cells inhibits eNOS activation by dephosphorylating Ser1177 and phosphorylating Thr495 (Michell et al., 2001). AMPK has been shown to phosphorylate Thr495in vitro (Chen et al., 1999); however, the same has not been demonstrated in vivo, indicating a conflicting role for AMPK in the regulation of eNOS activity. However, Chen et al. (2009) recently demonstrated that Ser633 phosphorylation could be important for endothelial NO production, and AMPK phosphorylates eNOS at Ser633 in endothelial cells to generate NO (Chen et al., 2009). Xiao et al. (2011) reported that ERK1/2 activation activates eNOS by enhancing Ser633 phosphorylation in response to endoplasmic reticulum Ca2+ release. Among the phosphatases, PP1 could dephosphorylate Thr495 to activate eNOS, while PP2A could dephosphorylate Ser1177 to inactivate eNOS (Fleming et al., 2001; Michell et al., 2001; Mount et al., 2007). Taken together these results indicate that upon activation in response to signalling stimuli, eNOS generates NO from L-arginine, one of the most common endogenous amino acids, in the presence of molecular oxygen and NADPH as substrates, and tetrahydrobiopterin (BH4), flavin adenine dinucleotide, flavin mononucleotide as cofactors (Palmer et al., 1988; Govers and Rabelink, 2001).

Table 2
Regulation of eNOS action by multiple protein kinases and phosphatases

The regulatory role of PPARγ in eNOS expression and activation and NO generation in conjunction with therapeutic potentials of PPARγ ligands in improving the function of vascular endothelium

PPARγ is mainly expressed in white and brown adipose tissue and also in endothelial cells and vascular smooth muscle cells (Tontonoz et al., 1995; Kota et al., 2005). As mentioned in the previous section, PPARγ agonists are used to specifically augment insulin sensitivity and to counter insulin resistance in T2DM patients. It is a clear that pharmacological agents that up-regulate and activate eNOS and enhance the generation and bioavailability of NO could be of therapeutic value in preventing the induction and progression of cardiovascular disorders, including atherosclerosis, hypertension and ischaemic heart disease. Recent studies have suggested a potential regulatory role of PPARγ on eNOS expression and activation and NO generation in the vascular endothelium. The following section addresses this imperative issue.

Administration of PPARγ activators such as rosiglitazone and pioglitazone in angiotensin-II-infused rats prevented the development of hypertension, reversed vascular remodelling, reduced vascular inflammation and improved endothelial function (Diep et al., 2004). Activation of PPARγ using 15-deoxy-δ-12,14-PGJ2 (15d-PGJ2) or ciglitazone was shown to stimulate the release of NO from the endothelium to protect the vascular wall (Calnek et al., 2003). Interestingly, this study demonstrated that the PPARγ-mediated release of NO might be independent of eNOS expression as both 15d-PGJ2 and ciglitazone did not alter eNOS mRNA levels. It was suggested that a direct transcriptional mechanism could have been involved in PPARγ-mediated release of NO in endothelial cells (Calnek et al., 2003). However, Polikandriotis et al. (2005) suggested that PPARγ activation could indirectly activate eNOS through a HSP90-dependent mechanism. The authors investigated the molecular mechanism underlying PPARγ activation-mediated increase in endothelial NO production. Treatment of human umbilical vein endothelial cells (HUVEC) with PPARγ agonists such as 15d-PGJ2, ciglitazone or rosiglitazone for 24 h was found to increase NO release. However, co-administration of GW9662, a selective PPARγ antagonist, inhibited the increase in NO release induced by 15d-PGJ2, ciglitazone or rosiglitazone implicating a key role for PPARγ in the induction of endothelial NO release (Polikandriotis et al., 2005). Interestingly, rosiglitazone and 15d-PGJ2, but not ciglitazone, stimulated HSP90–eNOS interaction, followed by eNOS activation (at Ser1177 phosphorylation). This suggests that PPARγ ligands have differential effects on eNOS-mediated release of NO from the endothelium. Moreover, in order to confirm the intermediate role of HSP90 in PPARγ activation-mediated eNOS activation and NO generation, the authors of this study investigated the effect of co-administration of the HSP90 inhibitor, geldanamycin; this was noted to attenuate 15d-PGJ2- and rosiglitazone-stimulated eNOS activation and NO release from endothelial cells, confirming the key role of HSP90 in this context (Polikandriotis et al., 2005).

The elevated vascular oxidative stress is known to reduce endothelial bioavailability of NO. The oxygen free radicals combine with NO to form peroxynitrite, resulting in the reduced bioavailability of NO (Ferdinandy and Schulz, 2003). Hwang et al. (2005) investigated the effect of PPARγ ligands on superoxide anion generation-induced NO metabolism. Treatment with 15d-PGJ2 or ciglitazone for 24 h decreased HUVEC membrane NADPH-dependent superoxide anion generation by reducing relative mRNA levels of the NADPH oxidase subunits such as nox-1, gp91phox (nox-2) and nox-4, which was accompanied by an enhanced expression of SOD. The authors suggested that, in addition to stimulating NO release from the endothelium, PPARγ activation could also enhance NO bioavailability by reducing endothelial superoxide anion generation and oxidative stress (Hwang et al., 2005). This study further revealed the underlying molecular mechanism involved in PPARγ-mediated regulation of NO physiology. Recently, it has been shown that oxidative stress attenuates PPARγ expression and activity in vascular endothelial cells through activation of inhibitory redox-regulated transcription factors and suppression of PPARγ transcription (Blanquicett et al., 2010). Thus, PPARγ agonists, through a reduction in oxidative stress as reported by Hwang et al., (2005), could activate their own PPARγ-mediated transcriptional programme for the regulation of the function of vascular endothelium.

Yuen et al. (2011) have recently suggested that PPARγ activation up-regulates eNOS expression. In this study, telmisartan, an AT1 receptor blocker having PPARγ agonistic property, inhibited vasoconstriction in mice resistance arteries that was noted to be mediated through a PPARγ-dependent increase in eNOS expression and activation, independent of its classical AT1 receptor blocking ability (Yuen et al., 2011). Likewise, Toyama et al. (2011) suggested a direct role of PPARγ in providing vascular protection in the obese type 2 diabetic db/db mouse. In this study, telmisartan was noted to significantly ameliorate VED and the reduction in eNOS phosphorylation/activation in diabetic db/db mice. However, co-administration of GW9662 abolished these protective effects of telmisartan against VED in diabetic db/db mice (Toyama et al., 2011), confirming the regulatory role of PPARγ in eNOS activation in providing vascular protection. In addition, treatment of Dahl salt-sensitive hypertensive rats with telmisartan effectively inhibited the vascular lesion formation such as medial thickness and perivascular fibrosis, but telmisartan plus GW9662 had no inhibitory effects, suggesting that the vasculoprotective effect of telmisartan is mediated through activation of PPARγ (Kobayashi et al., 2008). Moreover, telmisartan was noted to decrease plasma levels of asymmetric dimethyl-L-arginine (ADMA), an endogenous inhibitor of eNOS, and subsequently improve vascular function in patients with essential hypertension; an effect that might be mediated via its PPARγ activating property (Ono et al., 2009). Furthermore, Li et al. (2010) reported that the young male spontaneously hypertensive rat (SHR) showed significantly reduced expression of phosphotidylinositol 3-kinase (PI3K) and decreased phosphorylation of PKB-eNOS in vascular tissues. However, treatment with rosiglitazone increased vascular PPARγ expression, which was noted to be accompanied by restoration of PI3K/PKB/eNOS signalling activation, followed by improvement of endothelial function in the young SHR (Li et al., 2010).

Diabetes mellitus-induced VED is associated with elevated levels of advanced glycation end products (AGEs). Liang et al. (2009) showed that AGEs could cause apoptosis of endothelial progenitor cells (EPCs), resulting in dysfunction of these cells. These authors investigated the role of PPARγ activation in AGEs-induced dysfunction of EPCs. Interestingly, PPARγ activation by rosiglitazone reduced the apoptosis of EPCs and attenuated the dysfunction of EPCs induced by AGEs via up-regulation of PKB and eNOS signalling of EPCs (Liang et al., 2009). Likewise, PPARγ activation using pioglitazone up-regulated PKB and eNOS phosphorylation resulting in the amelioration of VED and enhancement of blood flow recovery after tissue ischaemia in the diabetic mouse (Huang et al., 2008).

The mechanism involved in PPARγ activation-mediated eNOS activation and improvement of endothelial function is not completely understood, although the key role of HSP90 was suggested by Polikandriotis et al. (2005) in this context. Additionally, Wong et al. (2011) have recently suggested that adiponectin, a hormonal protein secreted from adipose tissue, could play a key role in PPARγ activation-mediated eNOS activation and subsequent improvement of endothelial function. The authors demonstrated that PPARγ activation by rosiglitazone in the diabetic db/db mouse stimulated the release of adiponectin, which further activated AMPK/eNOS and cAMP/PKA signalling pathways in the aorta, resulting in a reduction in oxidative stress and the enhancement of NO bioavailability, leading to an improvement in endothelial function (Wong et al., 2011). Intriguingly, the authors observed that PPARγ activation restored the aortic endothelium-dependent relaxation in the diabetic mouse, whereas the diabetic mouse lacking adiponectin did not respond (Wong et al., 2011), suggesting strongly that adiponectin could mediate PPARγ-induced eNOS activation and NO generation to improve the function of the vascular endothelium.

It is well known that Rho-kinase, a serine–threonine kinase, plays a pivotal role in inducing VED by inactivating eNOS and reducing NO generation (Budzyn et al., 2006; Nohria et al., 2006). Intriguingly, Wakino et al. (2004) reported that activation of PPARγ inhibited Rho-kinase by up-regulating protein tyrosine phosphatase-2 (SHP-2). It should be noted that Vav, a GTP/GDP exchange factor, activates Rho-kinase. Thus Vav could be dephosphorylated by SHP-2. With this in mind, Wakino et al. (2004) convincingly demonstrated that PPARγ activation by pioglitazone in angiotensin-II-treated rat cultured aortic smooth muscle cells up-regulated SHP-2, which subsequently dephosphorylated Vav, resulting in inactivation of Rho-kinase. Importantly, Wakino et al. (2004) demonstrated that a similar mechanism was associated with PPARγ-mediated inhibition of Rho-kinase through up-regulation of SHP-2 in aortic tissues isolated from the SHR (Wakino et al., 2004). Taken together these findings indicate that PPARγ-mediated up-regulation and activation of eNOS could involve HSP90, adiponectin and a Rho-kinase associated signalling mechanism (Figure 1).

Figure 1
The cellular signalling system regulating PPARγ-mediated eNOS activity through phosphorylation/dephosphorylation at various sites of eNOS.

Is submaximal activation of PPARγ a valuable approach in the prevention of VED and VED-associated cardiovascular disorders?

The full agonists of PPARγ have been associated with severe adverse events. Although the adverse profiles of PPARγ agonists are highly disappointing, we cannot rule out the unexplored therapeutic potentials of pharmacological agents that differentially target PPARγ in improving cardiovascular abnormalities. It is a matter of debate as to what extent PPARγ needs to be activated to achieve a desirable insulin sensitizing effect and consequently avoid major adverse events. In fact, full agonists of PPARγ such as ciglitazone and troglitazone have already been withdrawn from the market, and the clinical use of rosiglitazone and pioglitazone for the treatment of T2DM is under question due to their adverse profiles. Rosiglitazone, a well-studied PPARγ agonist, has been withdrawn from the market in several countries due to an increased risk of cardiovascular events (Palee et al., 2011). We strongly believe that activating PPARγ at its maximal level may perhaps have undesirable effects on cardiovascular system, while submaximal/partial activation of PPARγ may have beneficial cardiovascular effects as seen with the telmisartan, a partial activator of PPARγ. Moreover, it is worth mentioning that the newly synthesized PPARγ partial agonists (Table 1 and Figure 2) such as balaglitazone, MBX-102, MK-0533, PAR-1622, PAM-1616, KR-62776 and SPPARγM5 have been reported to be devoid of or have a reduced tendency to cause the adverse effects associated with full agonist of PPARγ (Chang et al., 2008; Acton et al., 2009; Gregoire et al., 2009; Kim et al., 2009a,b; 2011; Henriksen et al., 2011). We, therefore, propose that pharmacological agents that submaximally activate PPARγ need to be further investigated for their possible cardiovascular protective potential. This contention has been convincingly delineated in the following section.

Figure 2
Chemical structures of pharmacological agents that submaximally activate PPARγ.

Telmisartan is a safe and long-acting AT1 receptor blocker effectively used as monotherapy for treating essential hypertension and hypertension-associated cardiovascular and renal disorders (Niegowska et al., 2005; Ruilope, 2011). The cardiovascular and renal functional improvements associated with telmisartan are not only mediated through its AT1 receptor blocking property but also through its partial PPARγ agonistic property (Benson et al., 2004; Schupp et al., 2004; Yamagishi and Takeuchi, 2005). It is worth noting that telmisartan affords cardiovascular protection exclusively through its ability to act as a partial PPARγ agonist, thereby activating eNOS and improving the endothelial function, independently of its AT1 receptor block properties (Kobayashi et al., 2008; Yuen et al., 2011). Telmisartan inhibited 9,11-dideoxy-11α,9α-epoxymethanoPGF (U46619)- or endothelin-1-induced contraction of mesenteric arteries from male C57BL/6J mice. However, this inhibition was found to be abolished in mesenteric arteries from eNOS-knockout or PPARγ-knockout mice (Yuen et al., 2011). Moreover, telmisartan-induced augmentation of eNOS expression and activation and NO production were reversed upon co-treatment with GW9662, a selective PPARγ antagonist. Interestingly, telmisartan-mediated eNOS activation through PPARγ activation was suggested to be unrelated to it antagonist effects on AT1 receptors (Yuen et al., 2011). This clearly indicates that telmisartan, through partial activation of PPARγ, thereby subsequently activating eNOS and generating NO in the vascular endothelium, has endothelial protective potential. Wenzel et al. (2008) demonstrated that telmisartan therapy reduced vascular oxidative stress, prevented the down-regulation of BH4-synthesizing enzyme (GTP-cyclohydrolase I) expression and inhibited eNOS uncoupling to prevent endothelial dysfunction in experimental diabetes mellitus. Moreover, the phosphorylation of eNOS at Ser1177 was noted to be decreased as a result of diabetes mellitus and this was considerably normalized by telmisartan therapy (Wenzel et al., 2008), explaining the beneficial effect of telmisartan in preventing diabetes mellitus-induced VED. A recent study confirmed that the vascular protective potential of telmisartan against diabetes mellitus-associated VED and associated vascular complications is predominantly mediated through its partial PPARγ activating property (Toyama et al., 2011). Telmisartan treatment of apolipoprotein E-deficient mice fed a high-fat diet was shown to significantly reduce blood pressure and considerably improve endothelial dysfunction (as assessed by the vasodilator response to acetylcholine) by modulating eNOS expression in the aorta; an effect that might be due to its action as a partial agonist of PPARγ (Nakagami et al., 2008). Moreover, telmisartan was suggested to enhance the bioavailability and vascular generation of NO through a PPARγ-mediated action (Ikejima et al., 2008). In this study, telmisartan was found to increase acetylcholine-mediated release of NO in genetically hyperlipidaemic rabbits [Watanabe heritable hyperlipidemic (WHHL) rabbits]; an effect that was abolished by co-treatment with the selective PPARγ antagonist, GW9662. Moreover, telmisartan decreased the atherosclerotic plaque area in the thoracic aorta of WHHL rabbits (Ikejima et al., 2008). A recent study revealed that telmisartan could protect against the impaired vasodilatation observed in genetically fatty rats with metabolic syndrome through its anti-oxidative and anti-nitrative stress properties (Kagota et al., 2011). Interestingly, the PPARγ-mediated vascular endothelial protective potential of telmisartan was confirmed by Ono et al. (2009) in patients with essential hypertension. Telmisartan improved VED by reducing ADMA, an eNOS inhibitor synthesized by endothelial cells, and decreasing pulse-wave velocity through its additional mechanism associated with PPARγ activation, independent of its AT1 receptor blockade-mediated hypotensive action (Ono et al., 2009). The leucocyte–endothelial interaction is a fundamental event in the induction and progression of atherosclerotic plaques. Cicha et al. (2011) demonstrated that telmisartan has ability to decrease TNF-α-induced recruitment of monocytic cells and endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells. However, the inhibitory effect of telmisartan on monocytic cell recruitment and VCAM-1 induction was found to be attenuated in the presence of the PPARγ antagonist, GW9662, suggesting a key role of PPARγ activation in this process. These authors suggested that this mechanism could possibly contribute to the beneficial effects of telmisartan in protecting atherosclerosis-prone arterial regions (Cicha et al., 2011). It is worth mentioning that telmisartan has the potential to down-regulate the expression of AT1 receptors both at the mRNA and protein levels in a dose- and time-dependent manner (Imayama et al., 2006). This study, intriguingly, demonstrated that telmisartan-induced down-regulation of AT1 receptors was mediated through its ability to activate PPARγ (Imayama et al., 2006). Thus, it is possible that submaximal activation of PPARγ could inhibit the detrimental effects of angiotensin-II on the cardiovascular system through down-regulation of AT1 receptors as well. Therefore, submaximal PPARγ activation could, in fact, be beneficial in preventing cardiovascular abnormalities associated with overactivation of the renin–angiotensin–aldosterone system (RAAS).

Statins are promising agents for improving vascular endothelial function and preventing the pathogenesis of atherosclerosis and hypertension and both-associated cardiovascular disease. We have recently suggested a potential interplay between statins and PPARs in preventing cardiovascular abnormalities (Balakumar and Mahadevan, 2012). It is noteworthy that treatment of mice deficient in LDL receptors and leptin (obese dyslipidemic mice with elevated blood pressure due to NO-sensitive blood pressure variability) with rosuvastatin normalized elevated blood pressure, independently of changes in plasma cholesterol, by up-regulating PPARγ in the aortic arch (Desjardins et al., 2008). However, GW9662 and siRNA raised against PPARγ prevented the blood pressure-lowering effect of rosuvastatin, suggesting that up-regulation of PPARγ in the endothelium could play an additional role in the vasculoprotective effects of rosuvastatin (Desjardins et al., 2008). This study strongly suggested that rosuvastatin regulates blood pressure homeostasis via a PPARγ-NO-dependent mechanism (Desjardins et al., 2008). In addition, the anti-atherogenic effect of atorvastatin in male Japanese rabbits fed high cholesterol was found to be associated with an increase in the expression of PPARγ, enhancement of NO concentration and decrease in plasminogen activator inhibitor-1 level (Yang et al., 2010). These studies suggest that the generation of NO and subsequent endothelial protection induced by statins could be mediated through a PPARγ signalling mechanism. Moreover, we have recently suggested that eNOS could play a pivotal role in mediating statins-associated cardiovascular protection (Balakumar et al., 2012).

Ischaemic pre- and post-conditioning are well-known endogenous cardioprotective methods (Balakumar and Babbar, 2012). It has been suggested that the inhibitory effect of lovastatin on the cardioprotective and infarct size-limiting potentials of ischaemic pre- and post-conditioning (Kocsis et al., 2008) could possibly involve an altered expression pattern of PPARγ (Onody et al., 2003), suggesting a possible adverse cross-talk modulation of PPARγ by statins.

Numerous studies have demonstrated the cardiovascular protective properties of red wine. Red wine polyphenols improved cardiovascular remodelling and vascular function in rats with NO-deficient hypertension. Furthermore, red wine significantly depresses experimental myocardial fibrosis and enhances endothelium-dependent relaxation in the aorta (Bernátováet al., 2002; Pechánováet al., 2004). Interestingly, the ameliorating effects of red wine on cardiometabolic disease have been shown to be partially associated with its ability to activate PPARγ (Zoechling et al., 2011). Some natural substances like curcumin have cardioprotective effects due to a potent anti-oxidant action (Miriyala et al., 2007). Interestingly, curcumin has the ability to activate PPARγ (Jacob et al., 2007). Therefore, it is possible that the PPARγ activating property of curcumin may play a role on its cardioprotective action; however, further studies are needed to prove this contention. Taken together, the pharmacological agents that submaximally activate PPARγ, as listed in Table 1, should be investigated to explore their potential in preventing cardiovascular disorders.

Concluding remarks

Discrepancies have persisted ever since the approval of thiazolidinedione-like PPARγ full agonists for the treatment of T2DM. PPARγ full agonists, indubitably, achieved their clinical target of enhancing insulin sensitivity and reducing hyperglycaemia in patients with T2DM. Unfortunately, these agents have been associated with serious adverse effects, including liver dysfunction, fluid retention, oedema and heart failure, leaving pioglitazone as the only thiazolidinedione suitable for the clinical use. However, the incidence of bladder cancer with pioglitazone has meant that there are now no thiazolidinediones available for clinical use to treat patients with T2DM. Moreover, a rosiglitazone-like full agonist of PPARγ has almost been withdrawn from the market due to its high incidence of cardiovascular side effects such as increased risk of coronary heart disease and heart attack. It seems that the road for full PPARγ agonists has comes to an end due to their undesirable side effects. However, telmisartan, being a partial PPARγ agonist, does not have such adverse side effects, and it has the potential to preventing the dysfunction of vascular endothelium and improve cardiovascular outcomes in patients with cardiovascular and renal abnormalities independently of its classical AT1 receptor blocking action. Therefore, it is plausible that partial/submaximal activation of PPARγ may have a selective vascular protective action devoid of the undesirable side effects associated with full PPARγ agonists. Furthermore, submaximal activation of PPARγ, by activating eNOS, generating NO, reducing oxidative stress, enhancing the bioavailability of NO and inhibiting the adhesion cascade and vascular inflammation, could have an important endothelial defensive action. The partial activation of PPARγ, as in the case of telmisartan, induces enough of an insulin sensitizing action (which might not be as marked as that of full PPARγ agonists), has a selective action on the regulation of vascular function and improves VED. In addition to telmisartan's submaximal action on PPARγ in preventing VED, another class of drugs, statins, have been shown to have vascular protective potential by a mechanism involving the up-regulation and activation of PPARγ. Therefore, developing a new generation of selective, partial PPARγ agonists that submaximally activate PPARγ may have important implications for the regulation of vascular endothelial function and may offer new perspectives for the treatment of VED and VED-associated cardiovascular disorders such as atherosclerosis, hypertension and coronary heart disease. In the light of this, an investigation into the vascular protective potentials of pharmacological agents that submaximally activate PPARγ such as balaglitazone, MBX-102, MK-0533, PAR-1622, PAM-1616, KR-62776 and SPPARγM5 (these compounds are devoid of or have a reduced tendency to cause the adverse side effects associated with full PPARγ agonists) is urgently needed.

Acknowledgments

We express our gratitude to Dr Rajendar Singh Sra, MD, Chairman, and Shri Om Parkash, Director, Rajendra Institute of Technology and Sciences, Sirsa, India, for their constant support for this study.

Glossary

ADMA
asymmetric dimethyl-L-arginine
AGEs
advanced glycation end products
AMPK
adenosine monophosphate-activated protein kinase
BH4
tetrahydrobiopterin
15d-PGJ2
15-deoxy-δ-12,14-PG J2
EDRF
endothelium-derived relaxing factor
eNOS
endothelial NOS
EPCs
endothelial progenitor cells
FAD
flavin adenine dinucleotide
FMN
flavin mononucleotide
HSP90
heat shock protein90
HUVEC
human umbilical vein endothelial cells
NADPH
nicotinamide adenine dinucleotide phosphate
ox-LDL
oxidized low-density lipoprotein
PAI-1
plasminogen activator inhibitor-1
PI3K
phosphotidylinositol 3-kinase
PP1
protein phosphatase 1
RAAS
renin-angiotensin-aldosterone system
SHP-2
protein tyrosine phosphatase-2
SOD
superoxide dismutase
T2DM
type 2 diabetes mellitus
VCAM-1
vascular cell adhesion molecule-1
VED
vascular endothelial dysfunction

Conflict of interest

No conflict of interest has been declared.

References

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