The Mechanism of Proinflammatory HDL Generation in Sickle Cell Disease Is Linked to Cell-Free Hemoglobin via Haptoglobin

PLOS ONE, Dec 2019

In sickle cell disease (SCD), the inflammatory properties of high-density lipoprotein (HDL) can be changed by cell-free hemoglobin (Hb), which is released into the blood during hemolysis. Hb in the plasma of SCD patients or mice can bind with HDL specifically inducing an inflammatory reaction. In our study, we found increased amounts of inflammatory factor proteins in the chronic oxidative state of SCD with higher levels of Hb, haptoglobin (Hp) and hemopexin (Hx) in the apolipoprotein A-I (ApoA-1) particles of HDL and the role of HDL is changed from being anti-inflammatory to proinflammatory. Our results also suggest Hp and Hx, the scavengers of Hb in HDL, are positively associated with inflammatory levels in SCD patients. HDL retained its inflammatory inhibition role in Hp−/− mice, with less Hb accumulation. Hx may further prevent inflammatory reaction because its level will be even higher when lack of Hx. We therefore demonstrated that Hp is indispensable during the process whereby Hb associates with HDL and plays a clear proinflammatory role. Therefore, it is essential to break the binding between Hb and Hp for treatment. The dissociation of Hb/Hp/Hx complexes may also play an important role in the study of other inflammatory angiogenesis-related diseases.

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The Mechanism of Proinflammatory HDL Generation in Sickle Cell Disease Is Linked to Cell-Free Hemoglobin via Haptoglobin

October The Mechanism of Proinflammatory HDL Generation in Sickle Cell Disease Is Linked to Cell-Free Hemoglobin via Haptoglobin Xiang Ji 0 1 Yimin Feng 1 Hui Tian 1 Wei Meng 1 4 Weiling Wang 0 1 Na Liu 1 3 Jun Zhang 0 1 Lingshu Wang 1 2 Jian Wang 0 1 Haiqing Gao 0 1 0 Geriatric Department Qilu Hospital of Shandong Univeristy; Shandong Key Laboratory of Proteomics , Jinan 250012, Shandong , China , 2 Clinical Laboratory, Qilu Hospital of Shandong Univeristy , Jinan 250012, Shandong, China, 3 ICU , The Affiliated Hospital of Qiingdao University , Qingdao 266012, Shandong , China 1 Editor: Christina Bursill, Heart Research Institute , AUSTRALIA 2 Endocrinology Department, Qilu Hospital of Shandong Univeristy , Jinan 250012, Shandong , China 3 Pharmacological Laboratory, Qilu Hospital of Shandong Univeristy , Jinan 250012, Shandong , China 4 Cardiology Department, Qilu Hospital of Shandong Univeristy , Jinan 250012, Shandong , China In sickle cell disease (SCD), the inflammatory properties of high-density lipoprotein (HDL) can be changed by cell-free hemoglobin (Hb), which is released into the blood during hemolysis. Hb in the plasma of SCD patients or mice can bind with HDL specifically inducing an inflammatory reaction. In our study, we found increased amounts of inflammatory factor proteins in the chronic oxidative state of SCD with higher levels of Hb, haptoglobin (Hp) and hemopexin (Hx) in the apolipoprotein A-I (ApoA-1) particles of HDL and the role of HDL is changed from being anti-inflammatory to proinflammatory. Our results also suggest Hp and Hx, the scavengers of Hb in HDL, are positively associated with inflammatory levels in SCD patients. HDL retained its inflammatory inhibition role in Hp−/− mice, with less Hb accumulation. Hx may further prevent inflammatory reaction because its level will be even higher when lack of Hx. We therefore demonstrated that Hp is indispensable during the process whereby Hb associates with HDL and plays a clear proinflammatory role. Therefore, it is essential to break the binding between Hb and Hp for treatment. The dissociation of Hb/Hp/ Hx complexes may also play an important role in the study of other inflammatory angiogenesis-related diseases. - OPEN ACCESS Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: This paper was supported by Shandong Province Outstanding Young Scientist Award Fund (BS2014YY021). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Background In 2016, American College of Cardiology (ACC) revealed the results of the ACCELERATE study and demonstrated once again that there was no benefit for patients if only HDLc can be increased by using a CETP inhibitor [ 1 ]. Among the explanations given by experts, one question tthat was raised was “Should HDL particles be the ‘good cholesterol’?”. Surprisingly, the answer might be ‘not always’ as HDL may be changed into a pro-inflammatory lipoprotein during an inflammatory response within the body. Sickle cell disease (SCD) is a form of hemoglobinopathy that is characterized by chronic hemolytic anemia, followed by a remarkable inflammatory response and oxidative stress within the circulation. Damaged sickle cells can release cell-free hemoglobin (cf-Hb) into the circulation, which induces hemoglobinuria, hypertension and pulmonary hypertension, along with other pathophysiological vascular changes. The symptoms of SCD begin in early childhood and last throughout life [ 2, 3 ]. However, the symptoms of SCD are closely related to vascular inflammation caused by abnormal HDL. Inflammation might be a more important factor than lipid infiltration for vascular lesions, even in atherosclerosis [4]. We have also reported that lower total cholesterol levels were found in the plasma of most people with SCD[ 5 ]. Recent studies have however demonstrated that the inflammatory properties of HDL impact the oxidative levels of SCD patients and animal models more significantly and with greater influence than does the amount of HDL [ 6, 7 ]. Healthy HDL can inhibit lowdensity lipoprotein (LDL) oxidation and other inflammatory complex formation. However, damaged HDL has the opposite effect and is considered to be a proinflammatory factor [8]. Although less commonly recognized, proinflammatory HDL (p-HDL) remains a good marker, emphasizing the role of HDL in the inflammatory process, in addition to the quantity of HDL [ 5 ]. Moreover, p-HDL contains lower levels of anti-inflammatory/oxidant proteins, such as apolipoprotein A-I (ApoA-I) and paraoxonase 1 (PON1) [ 9 ]. Effluxed cholesterol subsequently becomes reduced without sufficient ApoA-1 [ 10 ]. On the other hand, increased levels of heme, and other proinflammatory factors, act as an oxidant challenge to the HDL cargo. HDL theref (...truncated)


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Xiang Ji, Yimin Feng, Hui Tian, Wei Meng, Weiling Wang, Na Liu, Jun Zhang, Lingshu Wang, Jian Wang, Haiqing Gao. The Mechanism of Proinflammatory HDL Generation in Sickle Cell Disease Is Linked to Cell-Free Hemoglobin via Haptoglobin, PLOS ONE, 2016, Volume 11, Issue 10, DOI: 10.1371/journal.pone.0164264