TY - JOUR
T1 - Alagebrium in combination with exercise ameliorates age-associated ventricular and vascular stiffness
AU - Steppan, Jochen
AU - Tran, Huang
AU - Benjo, Alexandre M.
AU - Pellakuru, Laxsmi
AU - Barodka, Viachaslau
AU - Ryoo, Sungwoo
AU - Nyhan, Sineád M.
AU - Lussman, Craig
AU - Gupta, Gaurav
AU - White, Anthony R.
AU - Daher, Joao P.
AU - Shoukas, Artin A.
AU - Levine, Benjamin D.
AU - Berkowitz, Dan E.
N1 - Funding Information:
This work was supported by grants from the NIH , R01AG017479 (to BDL) and R01HL105296 (to DEB), as well as a grant from Alteon Corporation . Alteon had no input into the protocol design, data analysis, data presentation or manuscript preparation.
Funding Information:
This work was supported in part by a grant from Alteon Corporation, the makers of Alagebrium, which provided the drug only. Alteon had no input into the protocol design, data analysis, data presentation or manuscript preparation.
PY - 2012/8
Y1 - 2012/8
N2 - Advanced glycation end-products (AGEs) initiate cellular inflammation and contribute to cardiovascular disease in the elderly. AGE can be inhibited by Alagebrium (ALT), an AGE cross-link breaker. Moreover, the beneficial effects of exercise on aging are well recognized. Thus, we investigated the effects of ALT and exercise (Ex) on cardiovascular function in a rat aging model. Compared to young (Y) rats, in sedentary old (O) rats, end-systolic elastance (Ees) decreased (0.9±0.2 vs 1.7±0.4mmHg/μL, P<0.05), dP/dt max was attenuated (6054±685 vs 9540±939mmHg/s, P<0.05), ventricular compliance (end-diastolic pressure-volume relationship (EDPVR)) was impaired (1.4±0.2 vs 0.5±0.4mmHg/μL, P<0.05) and diastolic relaxation time (tau) was prolonged (21±3 vs 14±2ms, P<0.05). In old rats, combined ALT+Ex (4weeks) increased dP/dt max and Ees (8945±665 vs 6054±685mmHg/s, and 1.5±0.2 vs 0.9±0.2 respectively, O with ALT+Ex vs O, P<0.05 for both). Diastolic function (exponential power of EDPVR and tau) was also substantially improved by treatment with Alt+Ex in old rats (0.4±0.1 vs 0.9±0.2 and 16±2 vs 21±3ms, respectively, O with ALT+EX vs O, P<0.05 for both). Pulse wave velocity (PWV) was increased in old rats (7.0±0.7 vs 3.8±0.3ms, O vs Y, P<0.01). Both ALT and Ex alone decreased PWV in old rats but the combination decreased PWV to levels observed in young (4.6±0.5 vs 3.8±0.3ms, O with ALT+Ex vs Y, NS). These results suggest that prevention of the formation of new AGEs (with exercise) and breakdown of already formed AGEs (with ALT) may represent a therapeutic strategy for age-related ventricular and vascular stiffness.
AB - Advanced glycation end-products (AGEs) initiate cellular inflammation and contribute to cardiovascular disease in the elderly. AGE can be inhibited by Alagebrium (ALT), an AGE cross-link breaker. Moreover, the beneficial effects of exercise on aging are well recognized. Thus, we investigated the effects of ALT and exercise (Ex) on cardiovascular function in a rat aging model. Compared to young (Y) rats, in sedentary old (O) rats, end-systolic elastance (Ees) decreased (0.9±0.2 vs 1.7±0.4mmHg/μL, P<0.05), dP/dt max was attenuated (6054±685 vs 9540±939mmHg/s, P<0.05), ventricular compliance (end-diastolic pressure-volume relationship (EDPVR)) was impaired (1.4±0.2 vs 0.5±0.4mmHg/μL, P<0.05) and diastolic relaxation time (tau) was prolonged (21±3 vs 14±2ms, P<0.05). In old rats, combined ALT+Ex (4weeks) increased dP/dt max and Ees (8945±665 vs 6054±685mmHg/s, and 1.5±0.2 vs 0.9±0.2 respectively, O with ALT+Ex vs O, P<0.05 for both). Diastolic function (exponential power of EDPVR and tau) was also substantially improved by treatment with Alt+Ex in old rats (0.4±0.1 vs 0.9±0.2 and 16±2 vs 21±3ms, respectively, O with ALT+EX vs O, P<0.05 for both). Pulse wave velocity (PWV) was increased in old rats (7.0±0.7 vs 3.8±0.3ms, O vs Y, P<0.01). Both ALT and Ex alone decreased PWV in old rats but the combination decreased PWV to levels observed in young (4.6±0.5 vs 3.8±0.3ms, O with ALT+Ex vs Y, NS). These results suggest that prevention of the formation of new AGEs (with exercise) and breakdown of already formed AGEs (with ALT) may represent a therapeutic strategy for age-related ventricular and vascular stiffness.
KW - AGE
KW - Advanced glycation end-products
KW - Alagebrium
KW - Exercise
KW - Ventricular-vascular coupling
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U2 - 10.1016/j.exger.2012.04.006
DO - 10.1016/j.exger.2012.04.006
M3 - Article
C2 - 22569357
AN - SCOPUS:84863097526
SN - 0531-5565
VL - 47
SP - 565
EP - 572
JO - Experimental Gerontology
JF - Experimental Gerontology
IS - 8
ER -