Direct biomechanical induction of endogenous calcineurin inhibitor Down Syndrome Critical Region-1 in cardiac myocytes.
Signaling through the protein phosphatase calcineurin may play a critical role in cardiac hypertrophy. The gene for Down Syndrome Critical Region-1 (DSCR1) encodes a protein that is an endogenous calcineurin inhibitor. This study was designed to test the hypothesis that DSCR1 is directly induced by biomechanical stimuli. Neonatal rat cardiac myocytes were exposed to biaxial cyclic mechanical strain; mechanical strain upregulated DSCR1 mRNA expression in a time- and amplitude-dependent manner (3.4 +/- 0.2-fold at 8% strain for 6 h, n = 11, P < 0.01), and this induction was angiotensin II and endothelin I independent. Biomechanical induction of DSCR1 mRNA was partially blocked by calcineurin inhibition with cyclosporine A (30 +/- 5%, n = 3, P < 0.01). DSCR1 promoter-reporter experiments showed that mechanical strain induced DSCR1 promoter activity by 2.3-fold and that this induction was completely inhibited by cyclosporin A. Furthermore, DSCR1 gene expression was increased in the left ventricles of mice with pressure-overload hypertrophy induced by transverse aortic banding. These data demonstrate that biomechanical strain directly induces gene expression for the calcineurin inhibitor DSCR1 in cardiac myocytes, indicating that mechanically induced DSCR1 may regulate the hypertrophic response to mechanical overload.
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Partners Research Facility, 65 Lansdowne Street, Boston, MA 02115, USA.
Yanlin
Y
Wang
Gilles W
GW
De Keulenaer
Ellen O
EO
Weinberg
Suphi
S
Muangman
Antonio
A
Gualberto
Katherine T
KT
Landschulz
Thomas G
TG
Turi
John F
JF
Thompson
Richard T
RT
Lee
D000818:Animals; D019703:Calcineurin / Q000502:physiology; D002118:Calcium / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000502:physiology; D006973:Hypertension / Q000378:metabolism / Q000473:pathology; D006984:Hypertrophy; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013314:Stress, Mechanical
D016207:Cytokines; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D018377:Neurotransmitter Agents; C108612:RCAN1 protein, human; D012333:RNA, Messenger; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D019703:Calcineurin; D002118:Calcium