Apolipoprotein

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Apolipoprotein
PDB 1nfn EBI.jpg
Apolipoprotein e3 (Apoe3)
Identifiers
SymbolApolipoprotein
Pfam PF01442
InterPro IPR000074
SCOP2 1oef / SCOPe / SUPFAM
OPM superfamily 172
OPM protein 3r2p
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Apolipoproteins are proteins that bind lipids (oil-soluble substances such as fats, cholesterol and fat soluble vitamins) to form lipoproteins. They transport lipids in blood, cerebrospinal fluid and lymph.

Contents

The lipid components of lipoproteins are insoluble in water. However, because of their detergent-like (amphipathic) properties, apolipoproteins and other amphipathic molecules (such as phospholipids) can surround the lipids, creating a lipoprotein particle that is itself water-soluble, and can thus be carried through body fluids (i.e., blood, lymph).

In addition to stabilizing lipoprotein structure and solubilizing the lipid component, apolipoproteins interact with lipoprotein receptors and lipid transport proteins, thereby participating in lipoprotein uptake and clearance. They also serve as enzyme cofactors for specific enzymes involved in the metabolism of lipoproteins. [1]

Apolipoproteins are also exploited by hepatitis C virus (HCV) to enable virus entry, assembly, and transmission. They play a role in viral pathogenesis and viral evasion from neutralizing antibodies. [2]

Functions

Different lipoproteins contain different classes of apolipoproteins, which influence their function.

Apolipoprotein A-I (apoA1) is the major structural protein component of high-density lipoproteins (HDL), although it is present in other lipoproteins in smaller amounts. [3] Apolipoprotein A-IV (apoA4) is present in chylomicrons, very-low-density lipoproteins (VLDL), and HDL. It is thought to act primarily in reverse cholesterol transport [4] and intestinal lipid absorption via chylomicron assembly and secretion. ApoA-IV synthesized in hypothalamus is suggested to be a satiating factor which regulate the food intake of the rodent. [5] [1]

Apolipoprotein B plays a particularly important role in lipoprotein transport being the primary organizing protein of many lipoproteins. [1]

Apolipoprotein C-III (apoC3) plays an important role in lipid metabolism specific in regulating the metabolism of triglyceride-rich lipoproteins (TRLs). [6]

Apolipoprotein D (apoD) is a soluble carrier protein of lipophilic molecules in neurons and glial cells within the central and peripheral nervous system and apoD can also modulate the stability and oxidation status of these molecules. [7]

Apolipoprotein E (apoE) plays an important role in the transport and uptake of cholesterol by way of its high affinity interaction with lipoprotein receptors, including the low-density lipoprotein (LDL) receptor. ApoE is the major lipoprotein in the central nervous system. Recent findings with apoA1 and apoE suggest that the tertiary structures of these two members of the human exchangeable apolipoprotein gene family are related. [8] The three-dimensional structure of the LDL receptor-binding domain of apoE indicates that the protein forms an unusually elongated four-helix bundle that may be stabilised by a tightly packed hydrophobic core that includes leucine zipper-type interactions and by numerous salt bridges on the mostly charged surface. Basic amino acids important for LDL receptor binding are clustered into a surface patch on one long helix. [9]

Apolipoprotein F (apoF) is one of the minor apolipoprotein in blood plasma and it is a lipid transfer inhibit protein to inhibit cholesteryl ester transfer protein-mediated transfers of cholesteryl esters and triglycerides. [10] [11]

Apolipoprotein M (apoM) participates in the lipid metabolism and exhibit anti‑atherosclerotic functions and it is presented in high-density lipoprotein (HDL), low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL). [12]

Classes

There are multiple classes of apolipoproteins and several sub-classes:

Exchangeable apolipoproteins (apoA, apoC, and apoE) have the same genomic structure and are members of a multi-gene family that probably evolved from a common ancestral gene. Apo-AI and ApoA4 are part of the APOA1/C3/A4/A5 gene cluster on chromosome 11. [14]

Hundreds of genetic polymorphisms of the apolipoproteins have been described, and many of them alter their structure and function.

Evolution

The cluster of exchangeable apoliproteins is well conserved in vertebrates. [15] The family diversified by duplication, with the ancestral gene most similar to ApoC1. [16]

Beyond vertebrates, proteins similar to the exchangeable ApoA/C/E and the nonexchangable Apo-B are found in a wide range of animals and choanoflagellates. This suggests that the ancestral animal already has both kinds of apolipoproteins. In arthropods in particular, diacylglycerol-carrying apolipoproteins are known as apolipophorins, with the ApoA/C/E-like one known as apolipophorin III and the Apo-B like one known as apolipophorin I/II. [16]

Synthesis and regulation

Apolipoprotein synthesis in the intestine is regulated principally by the fat content of the diet.

Apolipoprotein synthesis in the liver is controlled by a host of factors, including dietary composition, hormones (insulin, glucagon, thyroxin, estrogens, androgens), alcohol intake, and various drugs (statins, niacin, and fibric acids). ApoB is an integral apoprotein whereas the others are peripheral apoproteins.

Apolipoprotein synthesis such as ApoA4 in hypothalamus involves in the integration of signals for regulation of food intake [5] which is regulated by vagal nerve and cholecystokinin. [17]

Disease

Apolipoprotein has been suggested to be implicated in several types of diseases and dysfunction.

ApoC1 level increases in neuropathic pain and fibromyalgia patients which suggest it plays an important role in occurrence of these conditions. [18]

ApoC3 is a risk factor of cardiovascular disease. Accumulation of plasma TRLs caused by elevated apoC-III leading to hypertriglyceridaemia. [19]

ApoD level increases in nervous system with a large number of neurologic disorders inclusive of Alzheimer's disease, schizophrenia, and stroke. [7]

ApoE has been implicated in dementia and Alzheimer's disease. [20]

Apo(a) is a component of lipoprotein(a) (Lp(a)) and elevated plasma Lp(a) level is a heritable, independent, and possibly causal risk factor for Atherosclerotic Cardiovascular Disease (ASCVD). [21] The cholesterol-rich apoB-containing lipoproteins also participate in the pathogenesis of ASCVD.

Related Research Articles

<span class="mw-page-title-main">Cholesterol</span> Sterol biosynthesized by all animal cells

Cholesterol is the principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils.

High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are typically composed of 80–100 proteins per particle. HDL particles enlarge while circulating in the blood, aggregating more fat molecules and transporting up to hundreds of fat molecules per particle.

<span class="mw-page-title-main">Low-density lipoprotein</span> One of the five major groups of lipoprotein

Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL). LDL delivers fat molecules to cells. LDL has been associated with the progression of atherosclerosis.

<span class="mw-page-title-main">Lipoprotein</span> Biochemical assembly whose purpose is to transport hydrophobic lipid molecules

A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, surrounded by a phospholipid outer shell, with the hydrophilic portions oriented outward toward the surrounding water and lipophilic portions oriented inward toward the lipid center. A special kind of protein, called apolipoprotein, is embedded in the outer shell, both stabilising the complex and giving it a functional identity that determines its role.

Very-low-density lipoprotein (VLDL), density relative to extracellular water, is a type of lipoprotein made by the liver. VLDL is one of the five major groups of lipoproteins that enable fats and cholesterol to move within the water-based solution of the bloodstream. VLDL is assembled in the liver from triglycerides, cholesterol, and apolipoproteins. VLDL is converted in the bloodstream to low-density lipoprotein (LDL) and intermediate-density lipoprotein (IDL). VLDL particles have a diameter of 30–80 nanometers (nm). VLDL transports endogenous products, whereas chylomicrons transport exogenous (dietary) products. In the early 2010s both the lipid composition and protein composition of this lipoprotein were characterised in great detail.

Hyperlipidemia is abnormally high levels of any or all lipids or lipoproteins in the blood. The term hyperlipidemia refers to the laboratory finding itself and is also used as an umbrella term covering any of various acquired or genetic disorders that result in that finding. Hyperlipidemia represents a subset of dyslipidemia and a superset of hypercholesterolemia. Hyperlipidemia is usually chronic and requires ongoing medication to control blood lipid levels.

Scavenger receptors are a large and diverse superfamily of cell surface receptors. Its properties were first recorded in 1970 by Drs. Brown and Goldstein, with the defining property being the ability to bind and remove modified low density lipoproteins (LDL). Today scavenger receptors are known to be involved in a wide range of processes, such as: homeostasis, apoptosis, inflammatory diseases and pathogen clearance. Scavenger receptors are mainly found on myeloid cells and other cells that bind to numerous ligands, primarily endogenous and modified host-molecules together with pathogen-associated molecular patterns(PAMPs), and remove them. The Kupffer cells in the liver are particularly rich in scavenger receptors, includes SR-A I, SR-A II, and MARCO.

<span class="mw-page-title-main">LDL receptor</span> Mammalian protein found in Homo sapiens

The low-density lipoprotein receptor (LDL-R) is a mosaic protein of 839 amino acids that mediates the endocytosis of cholesterol-rich low-density lipoprotein (LDL). It is a cell-surface receptor that recognizes apolipoprotein B100 (ApoB100), which is embedded in the outer phospholipid layer of very low-density lipoprotein (VLDL), their remnants—i.e. intermediate-density lipoprotein (IDL), and LDL particles. The receptor also recognizes apolipoprotein E (ApoE) which is found in chylomicron remnants and IDL. In humans, the LDL receptor protein is encoded by the LDLR gene on chromosome 19. It belongs to the low density lipoprotein receptor gene family. It is most significantly expressed in bronchial epithelial cells and adrenal gland and cortex tissue.

<span class="mw-page-title-main">Apolipoprotein E</span> Cholesterol-transporting protein most notably implicated in Alzheimers disease

Apolipoprotein E (Apo-E) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular diseases. It is encoded in humans by the gene APOE.

<span class="mw-page-title-main">Apolipoprotein B</span> Protein-coding gene in the species Homo sapiens

Apolipoprotein B (ApoB) is a protein that in humans is encoded by the APOB gene. It is commonly used to detect risk of atherosclerotic cardiovascular disease.

<span class="mw-page-title-main">VLDL receptor</span> Protein-coding gene in the species Homo sapiens

The very-low-density-lipoprotein receptor (VLDLR) is a transmembrane lipoprotein receptor of the low-density-lipoprotein (LDL) receptor family. VLDLR shows considerable homology with the members of this lineage. Discovered in 1992 by T. Yamamoto, VLDLR is widely distributed throughout the tissues of the body, including the heart, skeletal muscle, adipose tissue, and the brain, but is absent from the liver. This receptor has an important role in cholesterol uptake, metabolism of apolipoprotein E-containing triacylglycerol-rich lipoproteins, and neuronal migration in the developing brain. In humans, VLDLR is encoded by the VLDLR gene. Mutations of this gene may lead to a variety of symptoms and diseases, which include type I lissencephaly, cerebellar hypoplasia, and atherosclerosis.

<span class="mw-page-title-main">Familial hypercholesterolemia</span> Genetic disorder characterized by high cholesterol levels

Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein cholesterol, in the blood and early cardiovascular diseases. The most common mutations diminish the number of functional LDL receptors in the liver or produce abnormal LDL receptors that never go to the cell surface to function properly. Since the underlying body biochemistry is slightly different in individuals with FH, their high cholesterol levels are less responsive to the kinds of cholesterol control methods which are usually more effective in people without FH. Nevertheless, treatment is usually effective.

<span class="mw-page-title-main">Lipoprotein(a)</span> Low-density lipoprotein containing apolipoprotein(a)

Lipoprotein(a) is a low-density lipoprotein variant containing a protein called apolipoprotein(a). Genetic and epidemiological studies have identified lipoprotein(a) as a risk factor for atherosclerosis and related diseases, such as coronary heart disease and stroke.

<span class="mw-page-title-main">Apolipoprotein AI</span> Protein used in lipid metabolism

Apolipoprotein AI(Apo-AI) is a protein that in humans is encoded by the APOA1 gene. As the major component of HDL particles, it has a specific role in lipid metabolism.

<span class="mw-page-title-main">Hepatic lipase</span> Mammalian protein found in Homo sapiens

Hepatic lipase (HL), also called hepatic triglyceride lipase (HTGL) or LIPC (for "lipase, hepatic"), is a form of lipase, catalyzing the hydrolysis of triacylglyceride. Hepatic lipase is coded by chromosome 15 and its gene is also often referred to as HTGL or LIPC. Hepatic lipase is expressed mainly in liver cells, known as hepatocytes, and endothelial cells of the liver. The hepatic lipase can either remain attached to the liver or can unbind from the liver endothelial cells and is free to enter the body's circulation system. When bound on the endothelial cells of the liver, it is often found bound to heparan sulfate proteoglycans (HSPG), keeping HL inactive and unable to bind to HDL (high-density lipoprotein) or IDL (intermediate-density lipoprotein). When it is free in the bloodstream, however, it is found associated with HDL to maintain it inactive. This is because the triacylglycerides in HDL serve as a substrate, but the lipoprotein contains proteins around the triacylglycerides that can prevent the triacylglycerides from being broken down by HL.

Endothelial lipase (LIPG) is a form of lipase secreted by vascular endothelial cells in tissues with high metabolic rates and vascularization, such as the liver, lung, kidney, and thyroid gland. The LIPG enzyme is a vital component to many biological processes. These processes include lipoprotein metabolism, cytokine expression, and lipid composition in cells. Unlike the lipases that hydrolyze Triglycerides, endothelial lipase primarily hydrolyzes phospholipids. Due to the hydrolysis specificity, endothelial lipase contributes to multiple vital systems within the body. On the contrary to the beneficial roles that LIPG plays within the body, endothelial lipase is thought to play a potential role in cancer and inflammation. Knowledge obtained in vitro and in vivo suggest the relations to these conditions, but human interaction knowledge lacks due to the recent discovery of endothelial lipase. Endothelial lipase was first characterized in 1999. The two independent research groups which are notable for this discovery cloned the endothelial lipase gene and identified the novel lipase secreted from endothelial cells. The anti-Atherosclerosis opportunity through alleviating plaque blockage and prospective ability to raise High-density lipoprotein (HDL) have gained endothelial lipase recognition.

Blood lipids are lipids in the blood, either free or bound to other molecules. They are mostly transported in a phospholipid capsule, and the type of protein embedded in this outer shell determines the fate of the particle and its influence on metabolism. Examples of these lipids include cholesterol and triglycerides. The concentration of blood lipids depends on intake and excretion from the intestine, and uptake and secretion from cells. Hyperlipidemia is the presence of elevated or abnormal levels of lipids and/or lipoproteins in the blood, and is a major risk factor for cardiovascular disease.

<span class="mw-page-title-main">APOA5</span> Protein-coding gene in the species Homo sapiens

Apolipoprotein A-V is a protein that in humans is encoded by the APOA5 gene on chromosome 11. It is significantly expressed in liver. The protein encoded by this gene is an apolipoprotein and an important determinant of plasma triglyceride levels, a major risk factor for coronary artery disease. It is a component of several lipoprotein fractions including VLDL, HDL, chylomicrons. It is believed that apoA-V affects lipoprotein metabolism by interacting with LDL-R gene family receptors. Considering its association with lipoprotein levels, APOA5 is implicated in metabolic syndrome. The APOA5 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">LRP1</span> Mammalian protein found in Homo sapiens

Low density lipoprotein receptor-related protein 1 (LRP1), also known as alpha-2-macroglobulin receptor (A2MR), apolipoprotein E receptor (APOER) or cluster of differentiation 91 (CD91), is a protein forming a receptor found in the plasma membrane of cells involved in receptor-mediated endocytosis. In humans, the LRP1 protein is encoded by the LRP1 gene. LRP1 is also a key signalling protein and, thus, involved in various biological processes, such as lipoprotein metabolism and cell motility, and diseases, such as neurodegenerative diseases, atherosclerosis, and cancer.

<span class="mw-page-title-main">PCSK9</span> Mammalian protein found in humans

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the PCSK9 gene in humans on chromosome 1. It is the 9th member of the proprotein convertase family of proteins that activate other proteins. Similar genes (orthologs) are found across many species. As with many proteins, PCSK9 is inactive when first synthesized, because a section of peptide chains blocks their activity; proprotein convertases remove that section to activate the enzyme. The PCSK9 gene also contains one of 27 loci associated with increased risk of coronary artery disease.

References

  1. 1 2 Either roman numerals or arabic numbers may be used for gene family members. For example, apoA5 is also known as apo A-V.
  2. ↑ Isoforms from the same gene by alternative splicing.
  1. 1 2 3 Ramasamy I (December 2014). "Recent advances in physiological lipoprotein metabolism". Clinical Chemistry and Laboratory Medicine. 52 (12): 1695–727. doi: 10.1515/cclm-2013-0358 . PMID   23940067. S2CID   6925754.
  2. ↑ Wrensch F, Crouchet E, Ligat G, Zeisel MB, Keck ZY, Foung SK, et al. (2018). "Hepatitis C Virus (HCV)-Apolipoprotein Interactions and Immune Evasion and Their Impact on HCV Vaccine Design". Frontiers in Immunology. 9: 1436. doi: 10.3389/fimmu.2018.01436 . PMC   6021501 . PMID   29977246.
  3. ↑ von Zychlinski A, Williams M, McCormick S, Kleffmann T (June 2014). "Absolute quantification of apolipoproteins and associated proteins on human plasma lipoproteins". Journal of Proteomics. 106: 181–90. doi:10.1016/j.jprot.2014.04.030. PMID   24780726.
  4. ↑ Steinmetz A, Barbaras R, Ghalim N, Clavey V, Fruchart JC, Ailhaud G (May 1990). "Human apolipoprotein A-IV binds to apolipoprotein A-I/A-II receptor sites and promotes cholesterol efflux from adipose cells". The Journal of Biological Chemistry. 265 (14): 7859–63. doi: 10.1016/S0021-9258(19)39010-6 . PMID   2159462.
  5. 1 2 Liu M, Doi T, Shen L, Woods SC, Seeley RJ, Zheng S, et al. (May 2001). "Intestinal satiety protein apolipoprotein AIV is synthesized and regulated in rat hypothalamus". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 280 (5): R1382-7. doi:10.1152/ajpregu.2001.280.5.R1382. PMID   11294757.
  6. ↑ Ooi EM, Barrett PH, Chan DC, Watts GF (May 2008). "Apolipoprotein C-III: understanding an emerging cardiovascular risk factor". Clinical Science. 114 (10): 611–24. doi:10.1042/CS20070308. PMID   18399797.
  7. 1 2 Dassati S, Waldner A, Schweigreiter R (July 2014). "Apolipoprotein D takes center stage in the stress response of the aging and degenerative brain". Neurobiology of Aging. 35 (7): 1632–42. doi:10.1016/j.neurobiolaging.2014.01.148. PMC   3988949 . PMID   24612673.
  8. ↑ Saito H, Lund-Katz S, Phillips MC (July 2004). "Contributions of domain structure and lipid interaction to the functionality of exchangeable human apolipoproteins". Progress in Lipid Research. 43 (4): 350–80. doi:10.1016/j.plipres.2004.05.002. PMID   15234552.
  9. ↑ Wilson C, Wardell MR, Weisgraber KH, Mahley RW, Agard DA (June 1991). "Three-dimensional structure of the LDL receptor-binding domain of human apolipoprotein E". Science. 252 (5014): 1817–22. Bibcode:1991Sci...252.1817W. doi:10.1126/science.2063194. PMID   2063194.
  10. ↑ Wang X, Driscoll DM, Morton RE (January 1999). "Molecular cloning and expression of lipid transfer inhibitor protein reveals its identity with apolipoprotein F". The Journal of Biological Chemistry. 274 (3): 1814–20. doi: 10.1074/jbc.274.3.1814 . PMID   9880564.
  11. ↑ Koren E, McConathy WJ, Alaupovic P (October 1982). "Isolation and characterization of simple and complex lipoproteins containing apolipoprotein F from human plasma". Biochemistry. 21 (21): 5347–51. doi:10.1021/bi00264a035. PMID   6816269.
  12. ↑ Huang LZ, Gao JL, Pu C, Zhang PH, Wang LZ, Feng G, Zhang Y (August 2015). "Apolipoprotein M: Research progress, regulation and metabolic functions (Review)". Molecular Medicine Reports. 12 (2): 1617–24. doi: 10.3892/mmr.2015.3658 . PMID   25901639.
  13. ↑ Ağar C, de Groot PG, Levels JH, Marquart JA, Meijers JC (January 2009). "Beta2-glycoprotein I is incorrectly named apolipoprotein H". Journal of Thrombosis and Haemostasis. 7 (1): 235–6. doi: 10.1111/j.1538-7836.2008.03223.x . PMID   19017258. S2CID   43329586.
  14. ↑ Fullerton SM, Buchanan AV, Sonpar VA, Taylor SL, Smith JD, Carlson CS, et al. (June 2004). "The effects of scale: variation in the APOA1/C3/A4/A5 gene cluster". Human Genetics. 115 (1): 36–56. doi:10.1007/s00439-004-1106-x. PMID   15108119. S2CID   24857340.
  15. ↑ Babin PJ, Thisse C, Durliat M, Andre M, Akimenko MA, Thisse B (August 1997). "Both apolipoprotein E and A-I genes are present in a nonmammalian vertebrate and are highly expressed during embryonic development". Proceedings of the National Academy of Sciences of the United States of America. 94 (16): 8622–7. Bibcode:1997PNAS...94.8622B. doi: 10.1073/pnas.94.16.8622 . PMC   23048 . PMID   9238027.
  16. 1 2 Huebbe P, Rimbach G (August 2017). "Evolution of human apolipoprotein E (APOE) isoforms: Gene structure, protein function and interaction with dietary factors". Ageing Research Reviews. 37: 146–161. doi:10.1016/j.arr.2017.06.002. PMID   28647612. S2CID   3758905.
  17. ↑ Lo CC, Langhans W, Georgievsky M, Arnold M, Caldwell JL, Cheng S, et al. (December 2012). "Apolipoprotein AIV requires cholecystokinin and vagal nerves to suppress food intake". Endocrinology. 153 (12): 5857–65. doi:10.1210/en.2012-1427. PMC   3512075 . PMID   23027805.
  18. ↑ Lind, Anne-Li; Just, David; Mikus, Maria; Fredolini, Claudia; Ioannou, Marina; Gerdle, Björn; Ghafouri, Bijar; Bäckryd, Emmanuel; Tanum, Lars (2019-10-15). "CSF levels of apolipoprotein C1 and autotaxin found to associate with neuropathic pain and fibromyalgia". Journal of Pain Research. 12: 2875–2889. doi: 10.2147/jpr.s215348 . PMC   6800548 . PMID   31686904.
  19. ↑ Chan DC, Chen MM, Ooi EM, Watts GF (May 2008). "An ABC of apolipoprotein C-III: a clinically useful new cardiovascular risk factor?". International Journal of Clinical Practice. 62 (5): 799–809. doi: 10.1111/j.1742-1241.2007.01678.x . PMID   18201179. S2CID   34553066.
  20. ↑ Chang TY, Yamauchi Y, Hasan MT, Chang C (December 2017). "Cellular cholesterol homeostasis and Alzheimer's disease". Journal of Lipid Research. 58 (12): 2239–2254. doi: 10.1194/jlr.R075630 . PMC   5711498 . PMID   28298292.
  21. ↑ Wu MF, Xu KZ, Guo YG, Yu J, Wu Y, Lin LM (October 2019). "Lipoprotein(a) and Atherosclerotic Cardiovascular Disease: Current Understanding and Future Perspectives". Cardiovascular Drugs and Therapy. 33 (6): 739–748. doi:10.1007/s10557-019-06906-9. PMID   31655942. S2CID   204886420.
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