A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome

Elife. 2015 Oct 27;4:e08648. doi: 10.7554/eLife.08648.

Abstract

Calcium channel blockers (CCBs) are prescribed to patients with Marfan syndrome for prophylaxis against aortic aneurysm progression, despite limited evidence for their efficacy and safety in the disorder. Unexpectedly, Marfan mice treated with CCBs show accelerated aneurysm expansion, rupture, and premature lethality. This effect is both extracellular signal-regulated kinase (ERK1/2) dependent and angiotensin-II type 1 receptor (AT1R) dependent. We have identified protein kinase C beta (PKCβ) as a critical mediator of this pathway and demonstrate that the PKCβ inhibitor enzastaurin, and the clinically available anti-hypertensive agent hydralazine, both normalize aortic growth in Marfan mice, in association with reduced PKCβ and ERK1/2 activation. Furthermore, patients with Marfan syndrome and other forms of inherited thoracic aortic aneurysm taking CCBs display increased risk of aortic dissection and need for aortic surgery, compared to patients on other antihypertensive agents.

Keywords: Amlodipine; ERK; Hydralazine; Marfan syndrome; TGF-β signaling; Verapamil; aortic aneurysm; calcium channel blocker; chromosomes; genes; human; human biology; medicine; mouse; protein kinase C.

Publication types

  • Observational Study
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antihypertensive Agents / administration & dosage
  • Calcium Channel Blockers / adverse effects*
  • Calcium Channel Blockers / metabolism
  • Child
  • Child, Preschool
  • Disease Models, Animal
  • Humans
  • Hydralazine / administration & dosage
  • Indoles / administration & dosage
  • Longitudinal Studies
  • MAP Kinase Signaling System
  • Marfan Syndrome / drug therapy*
  • Marfan Syndrome / pathology*
  • Mice, Inbred C57BL
  • Protein Kinase C beta / metabolism
  • Receptor, Angiotensin, Type 1 / metabolism
  • Survival Analysis
  • Treatment Outcome

Substances

  • Agtr1a protein, mouse
  • Antihypertensive Agents
  • Calcium Channel Blockers
  • Indoles
  • Receptor, Angiotensin, Type 1
  • Hydralazine
  • Protein Kinase C beta
  • enzastaurin