Alterations of HDL’s to piHDL’s Proteome in Patients with Chronic Inflammatory Diseases, and HDL-Targeted Therapies

Abstract

Chronic inflammatory diseases, such as rheumatoid arthritis, steatohepatitis, periodontitis, chronic kidney disease, and others are associated with an increased risk of atherosclerotic cardiovascular disease, which persists even after accounting for traditional cardiac risk factors. The common factor linking these diseases to accelerated atherosclerosis is chronic systemic low-grade inflammation triggering changes in lipoprotein structure and metabolism. HDL, an independent marker of cardiovascular risk, is a lipoprotein particle with numerous important anti-atherogenic properties. Besides the essential role in reverse cholesterol transport, HDL possesses antioxidative, anti-inflammatory, antiapoptotic, and antithrombotic properties. Inflammation and inflammation-associated pathologies can cause modifications in HDL’s proteome and lipidome, transforming HDL from atheroprotective into a pro-atherosclerotic lipoprotein. Therefore, a simple increase in HDL concentration in patients with inflammatory diseases has not led to the desired anti-atherogenic outcome. In this review, the functions of individual protein components of HDL, rendering them either anti-inflammatory or pro-inflammatory are described in detail. Alterations of HDL proteome (such as replacing atheroprotective proteins by pro-inflammatory proteins, or posttranslational modifications) in patients with chronic inflammatory diseases and their impact on cardiovascular health are discussed. Finally, molecular, and clinical aspects of HDL-targeted therapies, including those used in therapeutical practice, drugs in clinical trials, and experimental drugs are comprehensively summarised.

HDL anti-inflammatory function is impaired and associated with high SAA1 and low APOA4 levels in aneurysmal subarachnoid hemorrhage

“…Both SAA1 and APOA4 play an important role in inflammation and the acute phase response. 51,52 As mentioned above, SAA1 has been consistently found in HDL from individuals with high cardiovascular risk and has been associated with loss of anti-inflammatory function. 53 The presence of SAA in HDL reduces their affinity for hepatocytes but increases their binding affinity to macrophages.…”

SARS‐CoV‐2 induced HDL dysfunction may affect the host's response to and recovery from COVID‐19

“…Interestingly, HDL increases the clearance of LPS via SR‐B1, which acts as an LPS‐binding protein 41 . Therefore, low HDL is negatively correlated with sepsis and augments systemic inflammatory reactions as HDL‐SR‐B1 acts as direct anti‐inflammatory agent‐driven cholesterol for glucocorticoid synthesis 62,63 . Van‐Leeuwen and colleagues observed that HDL serum levels rapidly declined in patients with severe sepsis, 64 suggesting a protective role of HDL against bacterial sepsis.…”

“…41 Therefore, low HDL is negatively correlated with sepsis and augments systemic inflammatory reactions as HDL-SR-B1 acts as direct anti-inflammatory agent-driven cholesterol for glucocorticoid synthesis. 62,63 Van-Leeuwen and colleagues observed that HDL serum levels rapidly declined in patients with severe sepsis, 64 suggesting a protective role of HDL against bacterial sepsis. Furthermore, it was observed that administration of reconstituted HDL can attenuate LPS-induced inflammation 64 proposed that HDL could be a valuable therapeutic approach for sepsis.…”

“…Thus, patients with co‐morbidities like hypertension and diabetes mellitus had low PON‐1 activity increasing their vulnerability for severe Covid‐19 124 . ApoAII inhibits the interaction between HDL and SR‐B1, displaces ApoA1 and impairs HDL function; it is regarded as an atherogenic factor and promotes pro‐inflammatory cytokines 62 . Therefore, ApoAII is increased in Covid‐19 patients, causing dysfunctional HDL development with immunoinflammatory complications 125 …”

A Current Update on the Role of HDL-Based Nanomedicine in Targeting Macrophages in Cardiovascular Disease

“…The alteration of HDL structure and function in disease is both an important biomarker of the diseased state as well as a potential critical factor influencing disease progression and regression [ 145 , 146 ]. Many post-translational modifications associated with inflammatory diseases render HDL-associated components dysfunctional and hence disrupt its normal functionality [ 147 ]. Figure 2 summarizes the modifications of selected HDL constituents in cardiovascular disease pathophysiology, highlighting its importance as a cause (therapeutic target) or consequence (diagnostic biomarker) of the disease.…”