p38 MAP kinase mediated proteoglycan synthesis as a target for the prevention of atherosclerosis.
The major underlying pathology of most cardiovascular disease is the chronic inflammatory disease of atherosclerosis. Type 2 diabetes, also recognised as an inflammatory condition, accelerates the development of atherosclerosis. Current therapies for atherosclerosis target risk factors such as elevated blood lipids and hypertension and are of strong but limited efficacy. The "response to retention" hypothesis states that atherosclerosis is initiated by the accumulation of lipids through binding to extracellular matrix, and this is specifically the glycosaminoglycan (GAG) chains on proteoglycans. Many vasoactive agonists stimulate changes in the structure of the GAGs which increase lipid binding and the relevant signalling pathways are a potential therapeutic target. It has recently been demonstrated that the actions of transforming growth factor beta on vascular smooth muscle proteoglycan synthesis involves signalling through p38 MAP kinase and inhibition of this pathway reduces binding of lipids. Inhibition of p38 MAP kinase will elicit a wide spread anti-inflammatory response which may alleviate some of the deleterious processes in cardiovascular tissues. This article explores the potential for the actions of p38 MAP kinase inhibitors directed at proteoglycan synthesis in vascular smooth muscle to contribute to the beneficial outcomes from targeting p38 MAP kinase for the prevention of cardiovascular disease.
Osman
Narin
N
Diabetes and Cell Biology Laboratory, BakerIDI Heart and Diabetes Institute, Postal, St. Kilda Rd Central, PO Box 6492, Melbourne, VIC 8008, Australia.
Ballinger
Mandy L
ML
Dadlani
Harsha M
HM
Getachew
Robel
R
Burch
Micah L
ML
Little
Peter J
PJ
D000818:Animals; D050197:Atherosclerosis / Q000150:complications / Q000503:physiopathology / Q000517:prevention & control*; D002318:Cardiovascular Diseases / Q000209:etiology / Q000517:prevention & control; D016503:Drug Delivery Systems; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011509:Proteoglycans / Q000096:biosynthesis / Q000187:drug effects; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D047428:Protein Kinase Inhibitors; D011509:Proteoglycans; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases