Everolimus Rescues the Phenotype of Elastin Insufficiency in Patient Induced Pluripotent Stem Cell-Derived Vascular Smooth Muscle Cells.

Abstract

OBJECTIVE:

Elastin gene deletion or mutation leads to arterial stenoses due to vascular smooth muscle cell (SMC) proliferation. Human induced pluripotent stem cells-derived SMCs can model the elastin insufficiency phenotype in vitro but show only partial rescue with rapamycin. Our objective was to identify drug candidates with superior efficacy in rescuing the SMC phenotype in elastin insufficiency patients. Approach and Results: SMCs generated from induced pluripotent stem cells from 5 elastin insufficiency patients with severe recurrent vascular stenoses (3 Williams syndrome and 2 elastin mutations) were phenotypically immature, hyperproliferative, poorly responsive to endothelin, and exerted reduced tension in 3-dimensional smooth muscle biowires. Elastin mRNA and protein were reduced in SMCs from patients compared to healthy control SMCs. Fourteen drug candidates were tested on patient SMCs. Of the mammalian target of rapamycin inhibitors studied, everolimus restored differentiation, rescued proliferation, and improved endothelin-induced calcium flux in all patient SMCs except one Williams syndrome. Of the calcium channel blockers, verapamil increased SMC differentiation and reduced proliferation in Williams syndrome patient cells but not in elastin mutation patients and had no effect on endothelin response. Combination treatment with everolimus and verapamil was not superior to everolimus alone. Other drug candidates had limited efficacy.

CONCLUSIONS:

Everolimus caused the most consistent improvement in SMC differentiation, proliferation and in SMC function in patients with both syndromic and nonsyndromic elastin insufficiency, and offers the best candidate for drug repurposing for treatment of elastin insufficiency associated vasculopathy.

• Authors: Caroline Kinnear, Rahul Agrawal, Caitlin Loo, Aric Pahnke, Deivid Carvalho Rodrigues, Tadeo Thompson, Oyediran Akinrinade, Samad Ahadian, Fred Keeley, Milica Radisic, Seema Mital, James Ellis
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 40 Issue 5 Pg. 1325-1339 (05 2020) ISSN: 1524-4636 [Electronic] United States
• PMID: 32212852 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ELN protein, human
• Protein Kinase Inhibitors
• Elastin
• Everolimus
• MTOR protein, human
• TOR Serine-Threonine Kinases

Topics

• Arterial Occlusive Diseases (drug therapy, genetics, metabolism, pathology)
• Case-Control Studies
• Cell Differentiation (drug effects)
• Cell Line
• Cell Proliferation (drug effects)
• Constriction, Pathologic
• Elastin (deficiency, genetics)
• Everolimus (pharmacology)
• Female
• Heterozygote
• Humans
• Induced Pluripotent Stem Cells (drug effects, metabolism, pathology)
• Infant
• Male
• Muscle, Smooth, Vascular (drug effects, metabolism, pathology)
• Mutation
• Myocytes, Smooth Muscle (drug effects, metabolism, pathology)
• Phenotype
• Protein Kinase Inhibitors (pharmacology)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Williams Syndrome (complications, genetics, metabolism)