Submaximal PPARΥ activation and endothelial dysfunction: New perspectives for the management of cardiovascular disorders

Abstract

PPARΥ activation plays an important role in glucose metabolism by enhancing insulin sensitization. PPARΥ is a primary target for thiazolidinedione-structured insulin sensitizers like pioglitazone and rosiglitazone employed for the treatment of type 2 diabetes mellitus. Additionally, PPARΥ activation inhibits adhesion cascades and detrimental vascular inflammatory events. Importantly, activation of PPARΥ 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 PPARΥ 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 PPARΥ full agonists, the therapeutic potential of novel pharmacological agents targeting PPARΥ submaximally cannot be ruled out. This review discusses the potential regulatory role of PPARΥ on eNOS expression and activation in improving the function of vascular endothelium. We argue that partial/submaximal activation of PPARΥ could be a major target for vascular endothelial functional improvement. Interestingly, newly synthesized partial agonists of PPARΥ such as balaglitazone, MBX-102, MK-0533, PAR-1622, PAM-1616, KR-62776 and SPPARΥM5 are devoid of or have a reduced tendency to cause the adverse effects associated with full agonists of PPARΥ. We propose that the vascular protective properties of pharmacological agents, which submaximally activate PPARΥ, should be investigated. Moreover, the therapeutic opportunities of agents that submaximally activate PPARΥ in preventing vascular endothelial dysfunction (VED) and VED-associated cardiovascular disorders are discussed. © 2012 The British Pharmacological Society.