A novel adenoviral gutless vector encoding sphingosine kinase promotes arteriogenesis and improves perfusion in a rabbit hindlimb ischemia model.

OBJECTIVES: We previously demonstrated that sphingosine kinase (SPK) increases the level of extracellular sphingosine-1-phosphate and promotes neovascularization in a mouse matrigel model. In this study, we tested the hypothesis that SPK gene transfer using a novel adenoviral 'gutless' vector (AGV) can enhance arteriogenesis in a rabbit hindlimb ischemia model. METHODS: Thirty-five male New Zealand white rabbits were randomized to the AGV-SPK group (n=13), AGV-null group (n=13), and control group (n=9). On day 10, after the induction of unilateral hindlimb ischemia, gene vectors or buffer were introduced and the effect examined on day 30, using calf blood pressure, quantitative angiographic analysis, and histology. RESULTS: Calf systolic blood pressure ratios of the ischemic limb to the normal limb on day 30 were 0.77+/-0.13 in control groups, including the AGV-null group, and 0.91+/-0.14 in the AGV-SPK group (P<0.05). Angiographic vessel counts were significantly increased (8.0+/-2.1 at baseline and 11.8+/-3.2 on day 30, P<0.001) in the AGV-SPK group. Histologic analysis showed that microscopic total vessel counts on day 30 were 3.5+/-1.8/field in the control and AGV-null group and 5.4+/-1.0/field in the AGV-SPK group. Arterioles (AGV-SPK; 3.0+/-0.8 versus control and AGV-null; 2.1+/-1.1, P<0.05) were significantly increased in the AGV-SPK group. CONCLUSIONS: This study shows that SPK promotes arteriogenesis, as evidenced by the maximal improvement in the blood pressure restoration and collateral vessel counts. SPK may be an important angiogenic target to improve perfusion in ischemic tissues.

Vulnerable atherosclerotic plaque: clinical implications.

Coronary Artery Disease (CAD) remains globally the leading cause of death and long-term morbidity. Among the many manifestations of CAD, acute coronary syndrome (ACS), ranging from unstable angina to acute myocardial infarction, is the most catastrophic event due to our inability to predict its occurrence. Despite improved treatments of CAD, ACS results in sudden death or permanent disability in a substantial percentage of patients. If we could predict the timing of ACS or better yet prevent its occurrence, we could alter the otherwise unfavorable course of CAD. Several studies have convincingly demonstrated that majority of all ACS develops from previously mild to moderate stenoses. Thus, based on these and autopsy studies, sudden disruption or rupture of the non-obstructive "vulnerable" atherosclerotic lesion is currently considered the cause of ACS. Recent clinical studies have substantiated earlier autopsy observations that plaque vulnerability is a systemic process, involving multiple locations concurrently. Although the exact inciting factors of the vulnerable plaque rupture are unknown, inflammation is accepted to be a pivotal event. The possibility of stabilizing the vulnerable plaques has strongly been supported by the lipid lowering trials, in which dramatic reduction of the acute coronary events was noted despite subtle improvements in luminal diameter. Furthermore, antiplatelet therapies have become an important preventative therapy due to the essential role of platelets in the aftermath of plaque rupture. Finally, various imaging modalities to diagnose the plaque vulnerability could help prevent the acute coronary events in the future.