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

Jefferson J Doyle1,2, Alexander J Doyle1,3, Nicole K Wilson1

  • 1Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States.

Elife
|October 28, 2015
PubMed

Insights

Calcium channel blockers worsen aortic aneurysms in Marfan syndrome mice by activating specific pathways. Treatments targeting protein kinase C beta (PKCβ) show promise for normalizing aortic growth.

Area of Science:

  • Cardiovascular Research
  • Genetics and Molecular Biology
  • Pharmacology

Background:

  • Calcium channel blockers (CCBs) are commonly prescribed for Marfan syndrome to prevent aortic aneurysm progression.
  • However, evidence supporting their efficacy and safety in this genetic disorder is limited.
  • Marfan syndrome is a heritable connective tissue disorder that affects the aorta.

Purpose of the Study:

  • To investigate the unexpected adverse effects of CCBs on aortic aneurysm progression in Marfan syndrome.
  • To identify the molecular pathways mediating CCB-induced aortic damage.
  • To evaluate potential therapeutic interventions for CCB-associated aortic complications.

Main Methods:

  • Utilized a mouse model of Marfan syndrome treated with CCBs.
  • Investigated the roles of extracellular signal-regulated kinase (ERK1/2) and angiotensin-II type 1 receptor (AT1R) pathways.
  • Identified protein kinase C beta (PKCβ) as a key mediator.
  • Tested the efficacy of a PKCβ inhibitor (enzastaurin) and hydralazine in normalizing aortic growth.
  • Analyzed clinical data from Marfan syndrome patients regarding CCB use and aortic events.

Main Results:

  • Marfan mice treated with CCBs exhibited accelerated aortic aneurysm expansion, rupture, and premature death.
  • These adverse effects were dependent on both ERK1/2 and AT1R activation.
  • PKCβ was identified as a critical mediator in this detrimental pathway.
  • Treatment with enzastaurin or hydralazine normalized aortic growth in Marfan mice.
  • These treatments were associated with reduced PKCβ and ERK1/2 activation.
  • Clinical data revealed an increased risk of aortic dissection and surgery in Marfan patients taking CCBs compared to other antihypertensives.

Conclusions:

  • CCBs can paradoxically accelerate aortic aneurysm progression in Marfan syndrome via PKCβ, ERK1/2, and AT1R pathways.
  • Targeting PKCβ with inhibitors like enzastaurin or using agents like hydralazine may offer therapeutic benefits.
  • Clinical findings suggest caution in using CCBs for Marfan syndrome patients, highlighting the need for alternative antihypertensive strategies.
Keywords:
AmlodipineERKHydralazineMarfan syndromeTGF-β signalingVerapamilaortic aneurysmcalcium channel blockerchromosomesgeneshumanhuman biologymedicinemouseprotein kinase C

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