Pathophysiology of isoprostanes in the cardiovascular system: implications of isoprostane‐mediated thromboxane A₂ receptor activation

Abstract

Isoprostanes are free radical-catalysed PG-like products of unsaturated fatty acids, such as arachidonic acid, which are widely recognized as reliable markers of systemic lipid peroxidation and oxidative stress in vivo. Moreover, activation of enzymes, such as COX-2, may contribute to isoprostane formation. Indeed, formation of isoprostanes is considerably increased in various diseases which have been linked to oxidative stress, such as cardiovascular disease (CVD), and may predict the atherosclerotic burden and the risk of cardiovascular complications in the latter patients. In addition, several isoprostanes may directly contribute to the functional consequences of oxidant stress via activation of the TxA2 prostanoid receptor (TP), for example, by affecting endothelial cell function and regeneration, vascular tone, haemostasis and ischaemia/reperfusion injury. In this context, experimental and clinical data suggest that selected isoprostanes may represent important alternative activators of the TP receptor when endogenous TxA2 levels are low, for example, in aspirin-treated individuals with CVD. In this review, we will summarize the current understanding of isoprostane formation, biochemistry and (patho) physiology in the cardiovascular context. IntroductionOxidative stress in biological systems is defined as an imbalance between the generation of reactive oxygen species (ROS) and antioxidant defence mechanisms (Dalle-Donne et al., 2006;Giustarini et al., 2009). In contrast to the physiological condition, during which ROS are only present at moderate levels and play an important role as messengers in redox signalling, in pathological conditions, when the physiological redox state of cells is disturbed, ROS can severely affect cellular signalling and function. Indeed, ROS which are not neutralized or scavenged by antioxidant molecules, such as GSH or superoxide dismutase, may react with nucleic acids and proteins and thereby alter the biochemical and physical properties of these important cellular components. Moreover, exposure of lipids to free radicals induces a non-enzymatic reaction cascade resulting in an increased formation of bioactive molecules named isoprostanes. Consequently, systemic isoprostane formation is significantly increased in a variety of pathological processes associated with oxidative stress, for example, cancer as well as, cardiovascular, metabolic and neurodegenerative diseases, and isoprostanes are increasingly recognized not only as markers of oxidative stress but also as mediators of disease progression (Praticò et al., 1997;Reilly et al., 1998;Davì et al., 1999;Minuz et al., 2002;Vassalle et al., 2003;Schwedhelm et al., 2004, Xia et al., 2005Montuschi et al., 2007;Schwedhelm et al., 2010; Barocas et al., 2011;Davies and Roberts, 2011; KhademAnsari et al., 2011;Montine et al., 2011;Sbardella et al., 2013). Isoprostanes are PG-like compounds derived from lipid peroxidation of esterified unsaturated fatty acids, for example, arachidonic acid, which are primarily generated in a free rad...

Thromboxane A2 Activates YAP/TAZ Protein to Induce Vascular Smooth Muscle Cell Proliferation and Migration

“…Increased formation of isoprostanes has been observed in diseases that are linked to oxidative stress, such as cardiovascular disease and cancer (52). As mentioned above, isoprostanes act, at least partially, via TP to exert their physiological effects.…”

“…Isoprostanes are prostaglandin-like compounds formed from the free radical-catalyzed peroxidation of unsaturated fatty acids, such as arachidonic acid, that are recognized not only as reliable markers of oxidative stress but also as important mediators of various diseases (52). Increased formation of isoprostanes has been observed in diseases that are linked to oxidative stress, such as cardiovascular disease and cancer (52).…”

Obstructive Sleep Apnea and Kidney Disease: A Potential Bidirectional Relationship?

“…[113][114][115][116][117] Plasma levels as well as exhaled breath condensate were significantly higher when measured in the morning (i.e., after sleep) in patients with OSA compared to age-and weight-matched healthy obese subjects, while evening levels of 8-Isoprostanes were similar in both groups. 118 The positive correlation between morning levels of 8-isoprostane and AHI suggested an association between OSA and increased systemic and local levels of oxidative stress.…”

Prostanoids and NSAIDs in Cardiovascular Biology and Disease

“…Versatility of signaling also results from cross binding of eicosanoids to different receptors. Thus, TP are activated by PGH2, PGE2, PGD2, and PGF2a, by 20-HETE, and, importantly, by isoprostanes [16,17]. Heterodimeric TPα/TPβdimers enhance isoprostane signaling whereas IP/TP heterodimers may downregulate TP signaling in response to PGI2 [18].…”

“…High C-reactive protein (CRP) inflammatory marker and CV risk factor disrupts thromboregulation by suppressing PGI2 synthase expression and increasing TP receptor expression in vascular injury [16,20]. TP signaling upregulates endothelial adhesion molecules and promotes infiltration of monocytes.…”