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.
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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)