PMID- 25512788
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20141216
LR  - 20220330
IS  - 1948-9358 (Print)
IS  - 1948-9358 (Electronic)
IS  - 1948-9358 (Linking)
VI  - 5
IP  - 6
DP  - 2014 Dec 15
TI  - Molecular mechanisms of AGE/RAGE-mediated fibrosis in the diabetic heart.
PG  - 860-7
LID - 10.4239/wjd.v5.i6.860 [doi]
AB  - Chronic hyperglycemia is one of the main characteristics of diabetes. Persistent 
      exposure to elevated glucose levels has been recognized as one of the major 
      causal factors of diabetic complications. In pathologies, like type 2 diabetes 
      mellitus (T2DM), mechanical and biochemical stimuli activate profibrotic 
      signaling cascades resulting in myocardial fibrosis and subsequent impaired 
      cardiac performance due to ventricular stiffness. High levels of glucose 
      nonenzymatically react with long-lived proteins, such as collagen, to form 
      advanced glycation end products (AGEs). AGE-modified collagen increase matrix 
      stiffness making it resistant to hydrolytic turnover, resulting in an 
      accumulation of extracellular matrix (ECM) proteins. AGEs account for many of the 
      diabetic cardiovascular complications through their engagement of the receptor 
      for AGE (RAGE). AGE/RAGE activation stimulates the secretion of numerous 
      profibrotic growth factors, promotes increased collagen deposition leading to 
      tissue fibrosis, as well as increased RAGE expression. To date, the AGE/RAGE 
      cascade is not fully understood. In this review, we will discuss one of the major 
      fibrotic signaling pathways, the AGE/RAGE signaling cascade, as well as propose 
      an alternate pathway via Rap1a that may offer insight into cardiovascular ECM 
      remodeling in T2DM. In a series of studies, we demonstrate a role for Rap1a in 
      the regulation of fibrosis and myofibroblast differentiation in isolated diabetic 
      and non-diabetic fibroblasts. While these studies are still in a preliminary 
      stage, inhibiting Rap1a protein expression appears to down-regulate the molecular 
      switch used to activate the zeta isotype of protein kinase C thereby promote 
      AGE/RAGE-mediated fibrosis.
FAU - Zhao, Jia
AU  - Zhao J
AD  - Jia Zhao, Rushil Randive, James A Stewart, Department of Biological Sciences, 
      Mississippi State University, Mississippi State, MS 39762, United States.
FAU - Randive, Rushil
AU  - Randive R
AD  - Jia Zhao, Rushil Randive, James A Stewart, Department of Biological Sciences, 
      Mississippi State University, Mississippi State, MS 39762, United States.
FAU - Stewart, James A
AU  - Stewart JA
AD  - Jia Zhao, Rushil Randive, James A Stewart, Department of Biological Sciences, 
      Mississippi State University, Mississippi State, MS 39762, United States.
LA  - eng
PT  - Journal Article
PT  - Review
PL  - United States
TA  - World J Diabetes
JT  - World journal of diabetes
JID - 101547524
PMC - PMC4265872
OTO - NOTNLM
OT  - Advanced glycation end product
OT  - Cardiac fibrosis
OT  - Extracellular matrix
OT  - Fibroblasts
OT  - Rap1a
OT  - Type 2 diabetes mellitus
EDAT- 2014/12/17 06:00
MHDA- 2014/12/17 06:01
PMCR- 2014/12/15
CRDT- 2014/12/17 06:00
PHST- 2014/08/29 00:00 [received]
PHST- 2014/09/23 00:00 [revised]
PHST- 2014/10/31 00:00 [accepted]
PHST- 2014/12/17 06:00 [entrez]
PHST- 2014/12/17 06:00 [pubmed]
PHST- 2014/12/17 06:01 [medline]
PHST- 2014/12/15 00:00 [pmc-release]
AID - 10.4239/wjd.v5.i6.860 [doi]
PST - ppublish
SO  - World J Diabetes. 2014 Dec 15;5(6):860-7. doi: 10.4239/wjd.v5.i6.860.