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

Abstract

BACKGROUND: High circulating levels of Lp(a) (lipoprotein[a]) increase the risk of atherosclerosis and calcific aortic valve disease, affecting millions of patients worldwide. Although atherosclerosis is commonly treated with low-density lipoprotein–targeting therapies, these do not reduce Lp(a) or risk of calcific aortic valve disease, which has no available drug therapies. Targeting Lp(a) production and catabolism may provide therapeutic benefit, but little is known about Lp(a) cellular uptake. METHODS: Here, unbiased ligand-receptor capture mass spectrometry was used to identify MFSD5 (major facilitator superfamily domain containing 5) as a novel receptor/cofactor involved in Lp(a) uptake. RESULTS: Reducing MFSD5 expression by a computationally identified small molecule or small interfering RNA suppressed Lp(a) uptake and calcification in primary human valvular endothelial and interstitial cells. MFSD5 variants were associated with aortic stenosis ( P =0.027 after multiple hypothesis testing) with evidence suggestive of an interaction with plasma Lp(a) levels. CONCLUSIONS: MFSD5 knockdown suppressing human valvular cell Lp(a) uptake and calcification, along with meta-analysis of MFSD5 variants associating with aortic stenosis, supports further preclinical assessment of MFSD5 in cardiovascular diseases, the leading cause of death worldwide.

Challenges and Opportunities in Valvular Heart Disease: From Molecular Mechanisms to the Community

“…35 In particular, sortilin is a mechanistically informative and diagnostically useful cardiovascular calcification target and may be a potent biomarker, as it is associated with aortic calcification and cardiovascular risk in men independently from C-reactive protein and LDL (low-density lipoprotein) cholesterol. Genome-wide association studies demonstrated an association of sortilin and MFSD5 with aortic stenosis in a large patient cohort, 33,34,36 thus substantiating these discoveries at the genomic level. With an increased availability of new drug targets coupled with the development of novel techniques of analyzing complex networks to prioritize drug targets for translation, clinical trials will continue to play a major role in validating future pharmacotherapies for multifactorial VHD diseases (Figure 2).…”

“…31 In addition, development of new disease models and new platforms to study and validate new targets are necessary. 32 Emerging single-cell and multi-omics platforms have already identified novel and clinically promising VHD drug targets, including monoamine oxidase, 33 MFSD5 (major facilitator superfamily domain containing 5), 34 and sortilin. 35 In particular, sortilin is a mechanistically informative and diagnostically useful cardiovascular calcification target and may be a potent biomarker, as it is associated with aortic calcification and cardiovascular risk in men independently from C-reactive protein and LDL (low-density lipoprotein) cholesterol.…”