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Published on: February 25, 2016
Overexpression of Nitric Oxide Synthase Restores Circulating Angiogenic Cell Function in Patients With Coronary
Qiumei Chen1, Monika Varga1, Xiaoyin Wang1
1Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA (Q.C., M.V., X.W., D.J.H., S.A., B.T.C., O.M.D., J.R.F., Y.Y., M.L.S.).
Insights
Age and coronary artery disease impair circulating angiogenic cells (CACs) function, limiting their therapeutic potential for heart attack (myocardial infarction) treatment. Gene therapy can potentially enhance CACs from older or diseased donors.
Area of Science:
- Cardiovascular Research
- Regenerative Medicine
- Cell Therapy
Background:
- Circulating angiogenic cells (CACs) are crucial for cardiovascular health and show therapeutic promise.
- Donor age and coronary artery disease (CAD) negatively impact CAC function and autologous cell therapy efficacy.
- Investigating the effects of age and CAD on CACs and potential gene therapy interventions is vital.
Purpose of the Study:
- To determine if age or CAD impairs the therapeutic potential of CACs for myocardial infarction (MI).
- To assess if ex vivo gene therapy overexpressing endothelial nitric oxide synthase (eNOS) can overcome these impairments.
Main Methods:
- Recruited 40 volunteers stratified by age and CAD status.
- Assessed CACs' functional capacity using migration, adherence, and nitric oxide (NO) production assays.
- Evaluated therapeutic potential by injecting varying-function CAC isolates into mouse hearts post-MI.
- Utilized adenovirus vectors for eNOS gene therapy (overexpression or knockdown) in CACs.
Main Results:
- Age and CAD were linked to reduced CAC migration and NO production.
- High-function CAC isolates significantly improved cardiac function post-MI in mice.
- Low-function CAC isolates showed minimal improvement compared to controls.
- eNOS gene therapy enhanced NO production, migration, and cardiac function in impaired CACs.
- eNOS knockdown in optimal CACs reduced their functional capabilities.
Conclusions:
- Age and CAD significantly impair CAC function, diminishing their therapeutic efficacy for MI.
- eNOS gene therapy presents a promising strategy to enhance CACs for autologous cell therapy in patients with cardiovascular risk factors.
- Targeting eNOS in CACs can restore or augment their regenerative capacity for treating heart disease.
Background:
Circulating angiogenic cells (CACs) are peripheral blood cells whose functional capacity inversely correlates with cardiovascular risk and that have therapeutic benefits in animal models of cardiovascular disease. However, donor age and disease state influence the efficacy of autologous cell therapy. We sought to determine whether age or coronary artery disease (CAD) impairs the therapeutic potential of CACs for myocardial infarction (MI) and whether the use of ex vivo gene therapy to overexpress endothelial nitric oxide (NO) synthase (eNOS) overcomes these defects.
Methods And Results:
We recruited 40 volunteers varying by sex, age (< or ≥45 years), and CAD and subjected their CACs to well-established functional tests. Age and CAD were associated with reduced CAC intrinsic migration (but not specific response to vascular endothelial growth factor, adherence of CACs to endothelial tubes, eNOS mRNA and protein levels, and NO production. To determine how CAC function influences therapeutic potential, we injected the 2 most functional and the 2 least functional CAC isolates into mouse hearts post MI. The high-function isolates substantially improved cardiac function, whereas the low-function isolates led to cardiac function only slightly better than vehicle control. Transduction of the worst isolate with eNOS cDNA adenovirus increased NO production, migration, and cardiac function of post-MI mice implanted with the CACs. Transduction of the best isolate with eNOS small interfering RNA adenovirus reduced all of these capabilities.
Conclusions:
Age and CAD impair multiple functions of CACs and limit therapeutic potential for the treatment of MI. eNOS gene therapy in CACs from older donors or those with CAD has the potential to improve autologous cell therapy outcomes.
