Crosslink breakers: a new approach to cardiovascular therapy.
OBJECTIVE
Advanced glycation end-products accumulate on body proteins with aging, and their formation is greatly enhanced with rising plasma glucose level. Advanced glycation end-products bond together and, consequently, increase protein crosslinking. In the circulatory system, increased collagen crosslinking caused by advanced glycation end-products increases cardiovascular stiffness as well as the risk for cardiovascular morbidity and mortality. A breaker of advanced glycation end-products-related crosslinks, ALT-711, has been recently discovered. This review summarizes the latest evidence that breaking collagen crosslinks may be an efficient new therapeutic approach to the adverse cardiovascular and renal consequences of aging and diabetes.


RESULTS
The results of recent studies clearly demonstrated that ALT-711, a breaker of advanced glycation end-products-related protein crosslinks, ameliorated the adverse cardiovascular and renal changes associated with aging, diabetes, and hypertension. In diabetic animals, ALT-711 improved left ventricular function, decreased ventricular collagen content and improved its solubility, reduced aortic stiffness, ameliorated diabetic nephrosclerosis, and improved renal function. In older spontaneously hypertensive rats, it reduced left ventricular mass and collagen content, reduced proteinuria, and extended survival. The results of recent studies also indicated that the effects of crosslinks breakers may be mediated in part via reduction in oxidative stress and profibrotic cytokines.


CONCLUSIONS
The results of experimental studies and one clinical trial have clearly established the usefulness of ALT-711 in the therapy of the cardiovascular and renal disorders associated with aging, diabetes, and hypertension. Thus, breaking advanced glycation end-products-related collagen crosslinks has emerged as a new approach to cardiovascular therapy.
Susic
Dinko
D
Hypertension Research Laboratory, Ochsner Clinic Foundation, New Orleans, Louisiana 70121, USA. dsusic@ochsner.org
Varagic
Jasmina
J
Ahn
Jwari
J
Frohlich
Edward D
ED
D000375:Aging; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000188:drug therapy*; D003094:Collagen / Q000378:metabolism*; D015897:Comorbidity; D003432:Cross-Linking Reagents / Q000378:metabolism; D003920:Diabetes Mellitus / Q000503:physiopathology; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000188:drug therapy*; D051381:Rats; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
D003432:Cross-Linking Reagents; D017127:Glycation End Products, Advanced; D013844:Thiazoles; D003094:Collagen; C406794:alagebrium