RAGE upregulation and nuclear factor-kappaB activation associated with ageing rat cardiomyocyte dysfunction.
Evidence suggests that ageing is a major risk factor for cardiac dysfunction. Interactions between advanced glycation endproducts (AGEs) and the receptor for AGEs (RAGE) are known to cause chronic cellular activation, including activation of nuclear factor-kappaB (NF-kappaB), which has been implicated as a causal factor in the ageing process. To assess whether cardiomyocyte contractile function and the interaction of AGEs with RAGE in the heart are altered in ageing, 25- and 2-month-old male rats were compared. Mechanical properties were assessed in ventricular myocytes using an edge-detection system, including peak twitch amplitude (PTA), time-to-PTA (TPS), time-to-75% relengthening (TR75) and maximal velocity of shortening/relengthening (+/-dL/dt) in ventricular myocytes. AGEs were detected by using a fluorescence assay. The expression of RAGE and NF-kappaB was assessed through a Western blot analysis. Compared with young myocytes, aged myocytes displayed a prolonged TR75 at 1 Hz. With increasing stimulus frequency (from 2 to 4 Hz), aged myocytes' PTA was significantly reduced relative to young myocytes. Aged rat hearts displayed high level of AGEs, RAGE upregulation and NF-kappaB activation. These findings demonstrate impaired cardiomyocyte relaxation and reduced tolerance to increased stimulus frequency in aged rats, which might be associated with enhanced AGEs, RAGE expression, and NF-kappaB activation.
Gao
Z Q
ZQ
Department of Toxicology, The Fourth Military Medical University, Xi'an, China.
Yang
C
C
Wang
Y Y
YY
Wang
P
P
Chen
H L
HL
Zhang
X D
XD
Liu
R
R
Li
W L
WL
Qin
X J
XJ
Liang
X
X
Hai
C X
CX
D000818:Animals; D001696:Biomechanical Phenomena; D016922:Cellular Senescence / Q000502:physiology*; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D015854:Up-Regulation
D017127:Glycation End Products, Advanced; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic