HDL-Induced Cell Signaling: Future Challenges and Opportunities

HDL constitutes a large and heterogenous macromolecule carrying more than 50 proteins, several amphipathic peptides, miRNAs, and hundreds of lipid species representing almost all known lipid classes. Several proteins and lipids identified in HDL—among others, apolipoprotein H, haptoglobin, and steroid hormones—are recognized receptor ligands and inductors of intracellular signaling events. However, the rigid evidence demonstrating that these proteins or lipids contribute to the HDL-induced signaling governing diverse functional responses to this lipoprotein has been not provided to date or is at best equivocal. For instance, several studies documented that HDL carries estradiol in the form of fatty acyl esters produced in a reaction catalyzed by LCAT. HDL-derived estradiol esters are internalized via SR-BI-mediated mechanisms and subsequently hydrolyzed intracellularly to unfold their effects. However, the specific signaling events and/or physiological effects clearly attributable to the estradiol content in HDL particles have not been unequivocally defined. In one study, HDL-associated estradiol was found to stimulate eNOS and vasodilation in an SR-BIand Akt-dependent manner, but these results were questioned by others (Gong et al. 2003; Nofer et al. 2004). In other study, dehydroepiandrosterone (DHEA) fatty acyl esters once incorporated in HDL were found to induce stronger vasodilatory response, and this effect appeared also to be mediated by SR-BI (Paatela et al. 2011). However, no clear signaling link between the HDL-associated DHEA and vasodilation has been established in this study. These two examples clearly show that the assignment of ligands present in HDL to the appending signaling machinery and to various functions exerted by these lipoproteins in physiology will be a major challenge in the future.

The composition of HDL particles is variable and influenced both by normal metabolism and in various states of pathology. For instance, HDL particles isolated from subjects suffering from acute or chronic inflammatory diseases were found to lose proteins and enzymes with established or presumed antiatherogenic function such as apoA-I or LCAT and to concomitantly acquire proinflammatory or prooxidative factors such as serum amyloid A (SAA), ceruloplasmin, lipoproteinspecific phospholipase A2, or myeloperoxidase. Not surprisingly, such inflammatory HDL particles are severely impeded in their capacity to trigger certain signaling pathways, but at the same time may acquire new ligands and thereby alter their signaling properties. For instance, the relatively high content of apolipoprotein J (apoJ) in HDL particles obtained from healthy subjects endowed them with important antiatherogenic property to promote endothelial survival by stimulation of the expression of antiapoptotic protein Bcl-XL (Riwanto et al. 2013). By contrast, HDL particles isolated from patients with stable coronary heart disease (CHD) or acute coronary syndromes were found to be poor in apoJ, but instead enriched in apoC-I or apoC-III (McNeal et al. 2013; Riwanto et al. 2013). Furthermore, the increased content of these apolipoproteins turned HDL particles into potent apoptosis inducers in vascular smooth muscle and endothelial cells by virtue of stimulating the expression of proapoptotic protein tBid. In addition to CHD, dysfunctional HDL is also encountered in chronic conditions such as chronic kidney disease (CKD). Abnormal HDL composition characterized primarily by increased serum amyloid A and apoC-III content as well as compromised HDL functionality has been repeatedly reported in uremic patients (Holzer et al. 2011; Weichhart et al. 2012). In one recent study, SAA-enriched HDL encountered in CKD was found to induce production of a proinflammatory chemokine MCP1 in smooth muscle cells by interaction with formyl peptide receptor 2 (FPR2) (To¨ lle et al. 2012). In other study conducted in CKD patients, accumulation of symmetric dimethylarginine (SDMA) in HDL was found to turn this lipoprotein into a noxious particle reducing NO bioavailability, evoking endothelial dysfunction, and subsequently increasing arterial blood pressure. The deleterious effects of SDMA-modified HDL were attributed to the noncanonical activation of TLR2 (Speer et al. 2013). This exemplifies another challenge facing HDL research in the future, namely, identification of ligands, receptors, and signaling cascades attributable to HDL in various states of pathology.

Notwithstanding the physiological or pathological character of HDL-induced signal transduction, its elucidation may open new opportunities for the development of antiatherogenic, anti-inflammatory, or antithrombotic drugs. Several interventional studies conducted recently and aiming at cardiovascular risk reduction through simple elevation of plasma HDL cholesterol fall through. This epic failure emphasizes the necessity to develop more sophisticated strategies based on targeted exploitation of selected antiatherogenic or anti-inflammatory activities exerted by HDL particles. The proper understanding of HDL-induced signaling may help to specifically enhance beneficial physiological or to disable harmful pathological effects of HDL and thereby to design more efficacious therapeutic approaches for cardiovascular and other inflammatory diseases.

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