Abstract
Ischemic heart disease (IHD) caused by atherosclerosis is the leading cause of death globally. Blood clots formed after the rupture of atherosclerotic plaques can cause complete blockage of the coronary artery, leading to myocardial infarction (MI) and even death. Promoting angiogenesis and restoring blood flow in the infarcted area is crucial for the repair of myocardial injury. Therefore, developing a safe, effective pro-angiogenic drug is urgently needed. Adenosine 3',5'-cyclic monophosphate (cAMP) is a cyclic nucleotide that acts as a key intracellular second messenger in numerous signal transduction pathways and regulates various cellular functions, including cell growth and differentiation, gene transcription and protein expression. Studies have shown that the extracellular cAMP (ex-cAMP) has been identified in several cell and tissue types, including the heart. The infusion of cAMP averted myocardial hypertrophy and fibrosis in a mouse heart failure model. Therefore, we hypothesize that ex-cAMP has proangiogenic effects in human endothelial cells. To test our hypothesis, we treated human umbilical vein endothelial cells (HUVEC) with cAMP (not able to cross the cell membrane) to determine the effects of ex-cAMP on EC proliferation, survival, migration, and angiogenesis using MTT, Brdu incorporation assay, wound scratch and tube formation. We found that ex-cAMP significantly increased HUVEC proliferation indicated by enhanced proliferation rate and Brdu incorporation. However, ex-cAMP has no effect on H 2 O 2 -induced EC death. ex-cAMP increased HUVEC migration by 30%. Importantly, ex-cAMP promoted robust tube formation (about 50%). Using western blot, we examined the role of ex-cAMP in the changes of Delta like 4-Notch signaling which is an essential signaling pathway for sprouting angiogenesis. Surprisingly, we did not observe any changes of Notch ligands (Dll4 and Jag1) and Notch1 receptor expression and activation. In conclusion, ex-cAMP demonstrated proangiogenic effects on HUVEC and these effects are Notch independent. Our findings shed light on the ex-cAMP as a potential potent therapeutical proangiogenetic drug that is safe, inexpensive, and stable.
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