Advertisement

Associations of HDL subclasses and lipid content with complement proteins over the menopause transition: The SWAN HDL ancillary study

HDL and complement proteins in women

      Highlights

      • Complement proteins C3 and C4 rise around the menopause transition (MT).
      • Changes in HDL over the MT may modulate inflammation.
      • Therapies impacting HDL may also impact immune response.

      Background

      The menopause transition (MT) could trigger low-grade chronic inflammation which may modify high-density lipoproteins (HDL) and lead to additional inflammatory responses contributing to atherosclerosis development.

      Objective

      To test whether complement proteins C3 and C4 increase around the final menstrual period (FMP), and whether changes in HDL subclasses and lipid content associate with C3 and C4 levels over time in midlife women.

      Methods

      The study included 471 women (at baseline: age 50.2(2.7) years; 87.3% pre or peri-menopausal) who had nuclear magnetic resonance spectroscopy HDL subclasses, lipid content, and C3 and C4 measured up to 5 times over the MT.

      Results

      Adjusted annual changes in C3 and C4 varied by time segments relative to FMP with significant increases, steeper for C3, only observed within 1 year before to 2 years after the FMP. Greater decreases in large HDL particles (HDL-P), HDL size, and HDL-phospholipids, and greater increases in small HDL-P and HDL-Triglycerides were associated with higher C3 and C4 over time, although associations with C4 were weaker than those with C3.

      Conclusion

      Complement proteins C3 and C4 significantly rise around menopause with C3 showing the steepest rise. Changes in HDL subclasses, overall size, and lipid content, over the MT may play a role in modulating inflammation responses known to be related to atherosclerosis. These results raise the possibility that novel therapeutic agents focusing on HDL might contribute to CVD protection by modulating inflammation.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Clinical Lipidology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Tall AR
        • Yvan-Charvet L.
        Cholesterol, inflammation and innate immunity.
        Nat Rev Immunol. 2015 Feb; 15: 104-116https://doi.org/10.1038/nri3793
        • Shah AS
        • Tan L
        • Long JL
        • Davidson WS.
        Proteomic diversity of high density lipoproteins: our emerging understanding of its importance in lipid transport and beyond.
        J Lipid Res. 2013 Oct; 54: 2575-2585https://doi.org/10.1194/jlr.R035725
        • Gordon SM
        • Davidson WS
        • Urbina EM
        • Dolan LM
        • Heink A
        • Zang H
        • et al.
        The effects of type 2 diabetes on lipoprotein composition and arterial stiffness in male youth.
        Diabetes. 2013 Aug; 62: 2958-2967https://doi.org/10.2337/db12-1753
        • Watanabe J
        • Charles-Schoeman C
        • Miao Y
        • Elashoff D
        • Lee YY
        • Katselis G
        • et al.
        Proteomic profiling following immunoaffinity capture of high-density lipoprotein: association of acute-phase proteins and complement factors with proinflammatory high-density lipoprotein in rheumatoid arthritis.
        Arthritis Rheum. 2012 Jun; 64: 1828-1837https://doi.org/10.1002/art.34363
        • Souza Junior DR
        • Silva ARM
        • Rosa-Fernandes L
        • Reis LR
        • Alexandria G
        • Bhosale SD
        • et al.
        HDL proteome remodeling associates with COVID-19 severity.
        J Clin Lipidol. 2021 Nov-Dec; 15: 796-804https://doi.org/10.1016/j.jacl.2021.10.005
        • Vaisar T
        • Pennathur S
        • Green PS
        • Gharib SA
        • Hoofnagle AN
        • Cheung MC
        • et al.
        Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL.
        J Clin Investig. 2007; 117: 746-756https://doi.org/10.1172/JCI26206
        • Speidl WS
        • Kastl SP
        • Huber K
        • Wojta J.
        Complement in atherosclerosis: friend or foe?.
        J Thromb Haemost. 2011; 9: 428-440https://doi.org/10.1111/j.1538-7836.2010.04172.x
        • El Khoudary SR
        • Aggarwal B
        • Beckie TM
        • Hodis HN
        • Johnson AE
        • Langer RD
        • et al.
        American Heart Association Prevention Science Committee of the Council on Epidemiology and Prevention; and Council on Cardiovascular and Stroke Nursing. Menopause Transition and Cardiovascular Disease Risk: Implications for Timing of Early Prevention: A Scientific Statement From the American Heart Association.
        Circulation. 2020 Dec 22; 142: e506-e532https://doi.org/10.1161/CIR.0000000000000912
        • El Khoudary SR
        • Chen X
        • Nasr AN
        • Billheimer J
        • Brooks MM
        • McConnell D
        • et al.
        HDL (High-Density Lipoprotein) Subclasses, Lipid Content, and Function Trajectories Across the Menopause Transition: SWAN-HDL Study.
        Arterioscler Thromb Vasc Biol. 2021 Feb; 41: 951-961https://doi.org/10.1161/ATVBAHA.120.315355
        • El Khoudary SR
        • Shields KJ
        • Chen HY
        • Matthews KA.
        Menopause, complement, and hemostatic markers in women at midlife: the Study of Women's Health Across the Nation.
        Atherosclerosis. 2013 Nov; 231: 54-58https://doi.org/10.1016/j.atherosclerosis.2013.08.039
        • Sowers M
        • Crawford S
        • Sternfeld B
        • Morganstein D
        • Gold E
        • Greendale GA
        • et al.
        SWAN: A multicenter, multiethnic, community-based cohort study of women and the menopausal transition.
        Menopause: Biology and Pathology. Academic Press, New York, NY2000: 175-180
        • Jeyarajah EJ
        • Cromwell WC
        • Otvos JD.
        Lipoprotein particle analysis by nuclear magnetic resonance spectroscopy.
        Clin Lab Med. 2006 Dec; 26: 847-870https://doi.org/10.1016/j.cll.2006.07.006
        • Freidwald WT
        • Levy RI
        • Frederickson DS.
        Estimation of the concentration of low density lipoprotein cholesterol in plasma.
        Clin Chem. 1972; 18: 499-501
        • Warnick GR
        • Albers JJ.
        A comprehensive evaluation of the heparin-manganese precipitation procedure for estimating high density lipoprotein cholesterol.
        J Lipid Res. 1978; 19: 65-76
        • Steiner P FJ
        • Bremner W
        • Stein E
        Standardization of micro-methods for plasma cholesterol, triglyceride and HDL-cholesterol with the Lipid Research Clinics’ methodology.
        J Clin Chem Clin Biochem. 1981; 19: 850
        • Ainsworth BE
        • Sternfeld B
        • Richardson MT
        • Jackson K.
        Evaluation of the kaiser physical activity survey in women.
        Med Sci Sports Exerc. 2000 Jul; 32: 1327-1338https://doi.org/10.1097/00005768-200007000-00022
        • Moreno-Navarrete JM
        • Fernández-Real JM.
        The complement system is dysfunctional in metabolic disease: Evidences in plasma and adipose tissue from obese and insulin resistant subjects.
        Semin Cell Dev Biol. 2019 Jan; 85: 164-172https://doi.org/10.1016/j.semcdb.2017.10.025
        • Onat A
        • Can G
        • Rezvani R
        • Cianflone K.
        Complement C3 and cleavage products in cardiometabolic risk.
        Clin Chim Acta. 2011 Jun 11; 412: 1171-1179https://doi.org/10.1016/j.cca.2011.03.005
        • Onat A
        • Uzunlar B
        • Hergenç G
        • Yazici M
        • Sari I
        • Uyarel H
        • et al.
        Cross-sectional study of complement C3 as a coronary risk factor among men and women.
        Clin Sci (Lond). 2005 Feb; 108: 129-135https://doi.org/10.1042/CS20040198
        • Nilsson B
        • Hamad OA
        • Ahlström H
        • Kullberg J
        • Johansson L
        • Lindhagen L
        • et al.
        C3 and C4 are strongly related to adipose tissue variables and cardiovascular risk factors.
        Eur J Clin Invest. 2014 Jun; 44: 587-596https://doi.org/10.1111/eci.12275
        • Xin Y
        • Hertle E
        • van der Kallen CJH
        • Vogelzangs N
        • Arts ICW
        • Schalkwijk CG
        • et al.
        C3 and alternative pathway components are associated with an adverse lipoprotein subclass profile: The CODAM study.
        J Clin Lipidol. 2021 Mar-Apr; 15: 311-319https://doi.org/10.1016/j.jacl.2021.01.011
        • Murray I
        • Sniderman AD
        • Cianflone K.
        Mice lacking acylation stimulating protein (ASP) have delayed postprandial triglyceride clearance.
        J Lipid Res. 1999 Sep; 40: 1671-1676
        • Barbu A
        • Hamad OA
        • Lind L
        • Ekdahl KN
        • Nilsson B.
        The role of complement factor C3 in lipid metabolism.
        Mol Immunol. 2015 Sep; 67: 101-107https://doi.org/10.1016/j.molimm.2015.02.027
        • Zhu X
        • Parks JS.
        New roles of HDL in inflammation and hematopoiesis.
        Annu Rev Nutr. 2012 Aug 21; 32: 161-182https://doi.org/10.1146/annurev-nutr-071811-150709
        • Szebeni J
        • Fontana JL
        • Wassef NM
        • Mongan PD
        • Morse DS
        • Dobbins DE
        • et al.
        Hemodynamic changes induced by liposomes and liposome-encapsulated hemoglobin in pigs: a model for pseudoallergic cardiopulmonary reactions to liposomes. Role of complement and inhibition by soluble CR1 and anti-C5a antibody.
        Circulation. 1999 May 4; 99: 2302-2309https://doi.org/10.1161/01.cir.99.17.2302
        • Moein Moghimi S
        • Hamad I
        • Bünger R
        • Andresen TL
        • Jørgensen K
        • Hunter AC
        • et al.
        Activation of the human complement system by cholesterol-rich and PEGylated liposomes-modulation of cholesterol-rich liposome-mediated complement activation by elevated serum LDL and HDL levels.
        J Liposome Res. 2006; 16: 167-174https://doi.org/10.1080/08982100600848801
        • De Nardo D
        • Labzin LI
        • Kono H
        • Seki R
        • Schmidt SV
        • Beyer M
        • et al.
        High-density lipoprotein mediates anti-inflammatory reprogramming of macrophages via the transcriptional regulator ATF3.
        Nat Immunol. 2014 Feb; 15: 152-160https://doi.org/10.1038/ni.2784
        • Dunbar RL
        • Gadi R
        • Bloedon L
        • Wolfe ML
        • Baer AL
        • Rader DJ
        • et al.
        Changes in High-Density Lipoprotein Cholesterol and Complement C3 are Strongly Inversely Correlated in the Setting of Niacin Therapy in Humans.
        Circulation. 2007; 116 (II_15)
        • Niyonzima N
        • Samstad EO
        • Aune MH
        • Ryan L
        • Bakke SS
        • Rokstad AM
        • et al.
        Reconstituted High-Density Lipoprotein Attenuates Cholesterol Crystal-Induced Inflammatory Responses by Reducing Complement Activation.
        J Immunol. 2015 Jul 1; 195: 257-264https://doi.org/10.4049/jimmunol.1403044
        • Uza G
        • Cristea A
        • Cucuianu MP.
        Increased level of the complement C3 protein in endogenous hypertriglyceridemia.
        J Clin Lab Immunol. 1982 Jun; 8 (PMID: 7108936): 101-105
        • Capuano V
        • D'Arminio T
        • La Sala G
        • Mazzotta G
        The third component of the complement (C3) is a marker of the risk of atherogenesis.
        Eur J Cardiovasc Prev Rehabil. 2006 Aug; 13 (PMID: 16874160): 658-660https://doi.org/10.1097/01.hjr.0000224485.80349.76
        • Seifert PS
        • Hansson GK.
        Complement receptors and regulatory proteins in human atherosclerotic lesions.
        Arteriosclerosis. 1989 Nov-Dec; 9 (PMID: 2480105): 802-811https://doi.org/10.1161/01.atv.9.6.802