A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome.
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.
Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States.|Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, United States.
Jefferson J
JJ
Doyle
Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States.|William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, United Kingdom.
Alexander J
AJ
Doyle
Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States.
Nicole K
NK
Wilson
Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States.|Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, United States.
Jennifer P
JP
Habashi
Department of Cardiology, Johns Hopkins University School of Medicine, Baltimore, United States.|Australian School of Advanced Medicine, Macquarie University, Sydney, Australia.
Djahida
D
Bedja
Research Triangle Institute International, Durham, United States.
Ryan E
RE
Whitworth
Thoracic Aortic Center, Departments of Medicine and Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
Mark E
ME
Lindsay
Department of Cardiovascular Surgery, Inselspital, Bern, Switzerland.|Proteomics Innovation Center in Heart Failure, Johns Hopkins University School of Medicine, Baltimore, United States.
Florian
F
Schoenhoff
Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States.
Loretha
L
Myers
Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States.
Nick
N
Huso
Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States.
Suha
S
Bachir
Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States.
Oliver
O
Squires
Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States.
Benjamin
B
Rusholme
Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, United States.
Hamid
H
Ehsan
Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, United States.
David
D
Huso
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Bethesda, United States.
Craig J
CJ
Thomas
William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, United Kingdom.
Mark J
MJ
Caulfield
Proteomics Innovation Center in Heart Failure, Johns Hopkins University School of Medicine, Baltimore, United States.
Jennifer E
JE
Van Eyk
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States.
Daniel P
DP
Judge
Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States.|Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, United States.|Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States.
Harry C
HC
Dietz
D000328:Adult; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage; D002121:Calcium Channel Blockers / Q000009:adverse effects* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D006801:Humans; D006830:Hydralazine / Q000008:administration & dosage; D007211:Indoles / Q000008:administration & dosage; D008137:Longitudinal Studies; D020935:MAP Kinase Signaling System; D008382:Marfan Syndrome / Q000188:drug therapy* / Q000473:pathology*; D008810:Mice, Inbred C57BL; D064546:Protein Kinase C beta / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D016019:Survival Analysis; D016896:Treatment Outcome
C544066:Agtr1a protein, mouse; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D007211:Indoles; D044140:Receptor, Angiotensin, Type 1; D006830:Hydralazine; D064546:Protein Kinase C beta; C504878:enzastaurin
Amlodipine; ERK; Hydralazine; Marfan syndrome; TGF-β signaling; Verapamil; aortic aneurysm; calcium channel blocker; chromosomes; genes; human; human biology; medicine; mouse; protein kinase C