Carvedilol Enhances Mesenchymal Stem Cell Therapy for Myocardial Infarction via Inhibition of Caspase-3 Expression

Abstract

Adult stem cells have shown great promise toward repairing infarcted heart and restoring cardiac function. Mesenchymal stem cells (MSCs), because of their inherent multipotent nature and their ability to secrete a multitude of growth factors and cytokines, have been used for cardiac repair with encouraging results. Preclinical studies showed that MSCs injected into infarcted hearts improve cardiac function and attenuate fibrosis. Although stem cell transplantation is a promising therapeutic option to repair the infarcted heart, it is faced with a number of challenges, including the survival of the transplanted cells in the ischemic region, due to excessive oxidative stress present in the ischemic region. The objective of this study was to determine the effect of Carvedilol (Carv), a nonselective ␤-blocker with antioxidant properties, on the survival and engraftment of MSCs in the infarcted heart. MSCs were subjected to a simulated host-tissue environment, similar to the one present in the infarcted myocardium, by culturing them in the presence of hydrogen peroxide (H 2 O 2 ) to induce oxidative stress. MSCs were treated with 2.5 M Carv for 1 h in serum-free medium, followed by treatment with H 2 O 2 for 2 h. The treated cells exhibited significant protection against H 2 O 2 -induced cell death versus untreated controls as determined by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assays. Likewise, transplantation of MSCs after permanent left coronary artery ligation and treatment of animals after myocardial infarction (MI) with Carv (5 mg/kg b.wt.) led to significant improvement in cardiac function, decreased fibrosis, and caspase-3 expression compared with the MI or MSC-alone groups.

Β-blockers treatment of cardiac surgery patients enhances isolation and improves phenotype of cardiosphere-derived cells

“…This study supports the possible predictive and adjuvant role of β-blocker treatment in cardiac cell therapy applications, as recently suggested for mesenchymal stem cell-based therapies61. It also suggests novel insights on the influence of BB treatments on the quality and abundance of the cardiac reparative cellular pool.…”

The birth of ‘regenerative pharmacology’: a clinical perspective

“…Also in tissue culture conditions carvidelol 2.5 mM was shown to reduce oxidative stress via inhibition of caspase-3 (a protein involved in cellular apoptosis). In animal models, this has lead to an improvement in ventricular function and reduced cardiac fibrosis, that is, positive remodelling (Hassan et al, 2012). Interestingly, no such benefits were observed with atenolol, suggesting that the protective effects of carvidelol were a result of its antioxidant properties either alone or in combination with b blockade (Sorrentino et al, 2011).…”

Estado actual de la terapia con células madre en el tratamiento de las cardiopatías: An update

“…Es necesario resaltar que la terapia celular es complementaria al tratamiento farmacológico convencional, habiéndose descrito su asociación sinérgica en estudios experimentales [77][78][79] . Finalmente, es importante mencionar que aunque la terapia celular representa un avance promisorio para la cardiología, aún quedan muchas dudas por resolver, incluyendo los criterios de selección de pacientes proclives a esta modalidad de tratamiento, las fuentes celulares a utilizar, vías de implante, cantidad de células a implantar y momento de su aplicación, entre otros.…”