Catalytic degradation of vitamin D up-regulated protein 1 mRNA enhances cardiomyocyte survival and prevents left ventricular remodeling after myocardial ischemia.
Vitamin D3 up-regulated protein 1 (VDUP1) is a key mediator of oxidative stress on various cellular processes via downstream effects on apoptosis signaling kinase 1 (ASK1) and p38 mitogen-activated protein kinase (MAPK). Here, we report that VDUP1 expression is significantly increased in rat hearts following acute myocardial ischemia, suggesting it may have important regulatory effects on cardiac physiological processes during periods of oxidative stress. Transfection of H9C2 cardiomyoblasts with a sequence-specific VDUP1 DNA enzyme to down-regulate VDUP1 mRNA expression significantly reduced apoptosis and enhanced cell survival under conditions of H(2)O(2) stress, and these effects involved inhibition of ASK1 activity. Direct intracardiac injection of the DNA enzyme at the time of acute myocardial infarction reduced myocardial VDUP1 mRNA expression and resulted in prolonged reduction in cardiomyocyte apoptosis and ASK1 activity. Moreover, down-regulation of VDUP1 was accompanied by significant reduction in cardiac expression of pro-collagen type I alpha2 mRNA level, as well as marked reduction in myocardial scar formation. These features were accompanied by significant improvement in cardiac function. Together, these results suggest a direct role for VDUP1 in the adverse effects of ischemia and oxidative stress on cardiomyocyte survival, left ventricular collagen deposition, and cardiac function. Strategies to inhibit VDUP1 expression and/or function during acute ischemic events may be beneficial to cardiac functional recovery and prevention of left ventricular remodeling.
Xiang
Guosheng
G
Department of Surgery, Columbia University Medical Center, New York, New York 10032, USA. gx15@columbia.edu
Seki
Tetsunori
T
Schuster
Michael D
MD
Witkowski
Piotr
P
Boyle
Andrew J
AJ
See
Fiona
F
Martens
Timothy P
TP
Kocher
Alfred
A
Sondermeijer
Hugo
H
Krum
Henry
H
Itescu
Silviu
S
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins; D002460:Cell Line; D002470:Cell Survival; D003094:Collagen / Q000378:metabolism; D021881:DNA, Catalytic / Q000378:metabolism; D066298:In Vitro Techniques; D017202:Myocardial Ischemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology*; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011923:Rats, Nude; D020257:Ventricular Remodeling / Q000235:genetics* / Q000502:physiology*
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D021881:DNA, Catalytic; D012333:RNA, Messenger; C493796:TXNIP protein, rat; D003094:Collagen