Biology Reference
In-Depth Information
Atherosclerosis is a progressive disease that evolves over a lifetime and ultimately
results in a fibrous plaque that protrudes into the arterial lumen (Madamanchi et al.
2005
). An atherosclerotic plaque poses several problems to the patient. Significant
narrowing of the artery can reduce downstream blood flow, especially during
elevated demand as occurs in walking and exercising. Maximal vasodilation may
be unable to compensate, resulting in a mismatch in oxygen supply and metabolic
demand, leading to ischemia and accumulation of metabolic byproducts that can
cause the symptoms of IC. In addition, atherosclerotic vasculature may have
reduced relaxation capacity (Barton and Haudenschild
2001
; Wang et al.
2002
)
further exacerbating the situation. The narrowing of the vessel also increases the
risk of thrombus development in low-shear zones downstream of the plaque
(Nesbitt et al.
2009
). Finally, an unstable plaque may rupture and the resulting
emboli may occlude arteries in other vascular sites. The rupture also exposes highly
prothrombogenic extracellular matrix components, including collagen, at the site,
and partial or complete thrombotic occlusion may occur.
3 PDE Expression and Effects of PDE Inhibition in Cells
Involved in Atherosclerosis
Cyclic nucleotides including cAMP and cGMP are major regulators of cellular
function in the cardiovascular system and likely influence atherosclerotic pathways.
Cyclic AMP and cGMP are produced by adenylyl and guanylyl cyclases (AC and
GC), respectively, and hydrolyzed by PDEs. The pharmacological inhibition of
PDEs increases intracellular levels of cyclic nucleotides. PDEs have been classified
into 11 genetically distinct families displaying different biochemical and pharma-
cological properties (Maurice et al.
2003
; Bender and Beavo
2006
; Conti and Beavo
2007
).
In this section, we discuss the expression of PDEs in platelets, vascular smooth
muscle cells (VSMCs), endothelium, and adipocytes, all major contributors to
atherosclerosis and thus potential mediators of PAD, including IC. PDE expression
in macrophages and the effects of PDE inhibitors on inflammatory pathways are
discussed in Page and Spina (
2011
).
3.1 Platelets
Platelets play an important role in normal hemostasis. They respond to leaks in the
circulation and, acting in synergy with the coagulation system, form a thrombus
to stop the bleeding. However, under pathophysiological conditions, activation of
platelets (including adhesion, degranulation, and aggregation) and generation of
thrombi may reduce/block blood flow causing ischemia. Thrombosis is often
