Annual Grant Winners 2003-2004
Ana Maria Castejon, Ph.D., HPD College of Pharmacy
Dean William Hardigan – HPD College of Pharmacy
Title: Mechanisms of Vascular Impairment
Induced by Withdrawal of Statins
Statins, are the most effective and widely used
lipid-lowering drugs. Statins are effective in primary
and secondary prevention of cardiac events in patients
with ischemic heart disease. Long-term treatment with statins
is commonly prescribed; however, nearly 1.2 % of subjects
receiving statin treatment develop requiring therapy discontinuation
complications (myopathy, rhabdomyolysis, liver dysfunction).
Recent studies in patients with coronary heart disease
reported that discontinuation of therapy with statins was
associated with increases in thrombotic vascular events
and of death or non-fatal myocardial infarction. The mechanisms
underlying these effects are unknown, although impaired
nitric oxide (NO) production by endothelial cells has been
described after discontinuation of statins. Because of
the relevance of these observations, we propose to investigate
how statin withdrawal induces vascular complications. The
study will be conducted in bovine endothelial cells and
in vascular smooth muscle cells in culture. The effects
of statin withdrawal on the production of vascular protective
and vascular deleterious substances will be investigated.
Specifically, we will determine the expression and levels
of NO, endothelin-1 (ET-1) and of the intercellular cell
adhesion molecule (ICAM-1) by the endothelium, and of angiotensin-II
AT1-receptor expression in vascular smooth muscle cells.
It is proposed that withdrawal of statins should lead to
activation of vasoconstrictor, mitogenic and inflammatory
markers (ET-1, AII, ICAM-1) and to reduction of the protective
action of NO.