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Major Facilitator Superfamily Domain Containing 5 Inhibition Reduces Lipoprotein(a) Uptake and Calcification in

Maximillian A Rogers1, Francesca Bartoli-Leonard1, Kang H Zheng1,2

  • 1Center for Interdisciplinary Cardiovascular Sciences (M.A.R., F.B.-L., K.H.Z., C.L.C., T.A., S.K., M.C.B., K.A.P., M.A., S.A.S., E.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Circulation
|November 8, 2023
PubMed

Insights

Researchers identified Major Facilitator Superfamily Domain Containing 5 (MFSD5) as a key player in lipoprotein(a) uptake. Targeting MFSD5 may offer new treatments for cardiovascular diseases like aortic stenosis.

Area of Science:

  • Cardiovascular Biology
  • Molecular Medicine

Background:

  • Elevated lipoprotein(a) [Lp(a)] is a significant risk factor for atherosclerosis and calcific aortic valve disease.
  • Current LDL-targeting therapies do not address Lp(a)-associated risks or calcific aortic valve disease, for which no drug therapies exist.
  • Understanding Lp(a) cellular uptake mechanisms is crucial for developing targeted therapies.

Approach:

  • Utilized unbiased ligand-receptor capture mass spectrometry to identify novel Lp(a) interaction partners.
  • Identified Major Facilitator Superfamily Domain Containing 5 (MFSD5) as a receptor/cofactor for Lp(a) uptake.
  • Investigated the functional role of MFSD5 in Lp(a) uptake and cellular calcification.

Key Points:

  • Reduced MFSD5 expression, via small molecules or siRNA, suppressed Lp(a) uptake and calcification in human valvular cells.
  • Genetic variants in MFSD5 were significantly associated with aortic stenosis.
  • Evidence suggests an interaction between MFSD5 variants and plasma Lp(a) levels in aortic stenosis.

Conclusions:

  • MFSD5 plays a critical role in mediating Lp(a) uptake and subsequent calcification in valvular cells.
  • The association of MFSD5 variants with aortic stenosis highlights its potential as a therapeutic target.
  • Further preclinical evaluation of MFSD5 is warranted for cardiovascular disease treatment strategies.
Abstract

Keywords:
Mfsd5 protein, humanaortic valve stenosislipoprotein(a)receptors, lipoproteinvascular calcification

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