Advanced glycation end products accumulate in vascular smooth muscle and modify vascular but not ventricular properties in elderly hypertensive canines.
BACKGROUND
Advanced glycation end products (AGEs) are believed to increase left ventricular (LV) and vascular stiffness, in part via cross-linking proteins. We determined whether and where AGEs were increased in elderly hypertensive nondiabetic dogs and whether an AGE cross-link breaker (ALT-711) improved vascular or ventricular function.


RESULTS
Elderly dogs with experimental hypertension (old hypertensives [OH]) were randomized to receive ALT-711 (OH+ALT group; n=11; 1 mg/kg PO) or not (OH group; n=11) for 8 weeks. Conscious blood pressure measurements (weekly), echocardiography (week 8), and anesthetized study (week 8) with LV pressure-volume analysis and aortic pressure-dimension and pressure-flow assessment over a range of preloads and afterloads were performed. In LV and aorta from OH, OH+ALT, and young normal dogs, AGE content (immunohistochemistry and Western analysis for N(epsilon)-(carboxymethyl)lysine [CML]) was assessed. Aortic CML content was markedly increased in OH and OH+ALT dogs compared with young normal dogs. CML was localized to aortic and aortic vasa vasorum smooth muscle but not to collagen or elastin. CML was essentially undetectable in young normal, OH, or OH+ALT myocardium but was visible in large vessels in the LV. ALT-711 therapy was associated with lower blood pressure and pulse pressure, decreased systemic vascular resistance, increased aortic distensibility and arterial compliance, and, notably, significant aortic dilatation. Neither LV systolic nor diastolic function was different in OH+ALT versus OH dogs.


CONCLUSIONS
In elderly hypertensive canines, AGE accumulation and AGE cross-link breaker effects were confined to the vasculature without evidence of myocardial accumulation or effects. The lack of AGE accumulation in collagen-rich areas suggests that the striking vascular effects may be mediated by mechanisms other than collagen cross-linking.
Shapiro
Brian P
BP
Cardiorenal Research Laboratory, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.
Owan
Theophilus E
TE
Mohammed
Selma F
SF
Meyer
Donna M
DM
Mills
Lisa D
LD
Schalkwijk
Casper G
CG
Redfield
Margaret M
MM
D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004549:Elastin / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D013844:Thiazoles / Q000494:pharmacology*; D014651:Vasa Vasorum / Q000378:metabolism / Q000473:pathology; D014655:Vascular Resistance / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects*
D017127:Glycation End Products, Advanced; D013844:Thiazoles; C048496:N(6)-carboxymethyllysine; D003094:Collagen; D004549:Elastin; C406794:alagebrium; D008239:Lysine