Nucleic acid therapeutics

Atherosclerosis arises from an excessive fibroproliferative-inflammatory response to injury of the artery wall and typically evolves over decades (1). Smooth muscle cells play a central role in the development of atherosclerotic lesions. Their ability to migrate from the medial compartment of the artery wall to the intima, where they proliferate, accumulate lipid, and generate extracellular matrix, is key to the development of occlusive vascular lesions. A common intervention for treating arterial blockage is percutaneous transluminal coronary angioplasty, in which an inflatable balloon is positioned at the site of arterial narrowing and used to physically disrupt the local atherosclerotic plaque. While angioplasty usually provides immediate symptomatic relief, its longer-term benefits are limited in a large proportion of cases (30–50% within 6 months) because the treated artery once again narrows at the site of inflation (2). This process, termed restenosis, involves elastic recoil, in the first instance, followed by extensive replication and remodeling — mainly by smooth muscle cells, which lay down matrix and eventually decrease luminal diameter at the site of ballooning. Most angioplasties are now performed in conjunction with the local deployment of metallic stents (3), which provide structural support in the reopened vessel by helping to prevent vascular recoil (4, 5). Pharmacologic agents able to decrease the incidence of restenosis in human subjects are extremely limited, with antiplatelet glycoprotein IIb/IIIa receptor antagonists (inhibitors of platelet aggregation and thrombus formation) providing most utility. Intracoronary radiation, antioxidants, and growth factor antagonists have also shown promise as inhibitors of restenosis (6). The hunt for efficient inhibitors of restenosis remains an ongoing challenge. Here, I review the transcriptional control of specific genes that regulate smooth muscle cell biology, and I discuss the use of novel nucleic acid–based therapeutics that might be employed at the time of treatment to block restenosis over the long term. Activation of Egr-1 in response to injury Cell movement, proliferation, and extracellular matrix deposition in the injured artery wall are mediated by the local activity of growth factors, cytokines, and other regulatory molecules. Mechanical injury activates signaling and transcriptional pathways that converge at the promoters of many genes whose products then influence the development of lesions. Insights into the molecular mechanisms associated with the transcriptional response to injury derive from a wealth of rat and other animal studies involving balloon catheter injury. As seen in these models, injury to the artery wall results in the rapid activation of mitogen-activated protein kinase subclasses, such as extracellular signal–regulated kinase (ERK) and stress-activated protein kinase/c-Jun NH2-terminal protein kinase (JNK), as well as a multitude of transcription factors (Table 1), including early growth response factor-1 (Egr-1) (7, 8).