Although clinical trials of autologous whole bone marrow for cardiac repair demonstrate promising results, many practical and mechanistic issues regarding this therapy remain highly controversial. Here, we report the results of a randomized study of bone-marrow-derived mesenchymal stem cells, administered to pigs, which offer several new insights regarding cellular cardiomyoplasty. First, cells were safely injected by using a percutaneous-injection catheter 3 d after myocardial infarction. Second, cellular transplantation resulted in long-term engraftment, profound reduction in scar formation, and near-normalization of cardiac function. Third, transplanted cells were preprepared from an allogeneic donor and were not rejected, a major practical advance for widespread application of this therapy. Together, these findings demonstrate that the direct injection of cellular grafts into damaged myocardium is safe and effective in the periinfarct period. The direct delivery of cells to necrotic myocardium offers a valuable alternative to intracoronary cell injections, and the use of allogeneic mesenchymal stem cells provides a valuable strategy for cardiac regenerative therapy that avoids the need for preparing autologous cells from the recipient.
Saliaris AP, Amado LC, Minhas KM, Schuleri KH, Lehrke S, John MS, Fitton T, Barreiro C, Berry C, Zheng M, Kozielski K, Eneboe V, Brawn J, Hare JM. Chronic allopurinol administration ameliorates maladaptive alterations in Ca 2ϩ cycling proteins and -adrenergic hyporesponsiveness in heart failure. Am J Physiol Heart Circ Physiol 292: H1328 -H1335, 2007. First published October 27, 2006; doi:10.1152/ajpheart.00461.2006.-Xanthine oxidase (XO) activity contributes to both abnormal excitation-contraction (EC) coupling and cardiac remodeling in heart failure (HF). -Adrenergic hyporesponsiveness and abnormalities in Ca 2ϩ cycling proteins are mechanistically linked features of the HF phenotype. Accordingly, we hypothesized that XO influences -adrenergic responsiveness and expression of genes whose products participate in deranged EC coupling. We measured inotropic (dP/dt max), lusitropic (), and vascular (elastance; E a) responses to -adrenergic (-AR) stimulation with dobutamine in conscious dogs administered allopurinol (100 mg po daily) or placebo during a 4-wk induction of pacing HF. With HF induction, the decreases in both baseline and dobutamine-stimulated inotropic responses were offset by allopurinol. Additionally, allopurinol converted a vasoconstrictor effect to dobutamine to a vasodilator response and enhanced both lusitropic and preload reducing effects. To assess molecular correlates for this phenotype, we measured myocardial sarcoplasmic reticulum Ca 2ϩ -ATPase 2a (SERCA), phospholamban (PLB), phosphorylated PLB (P-PLB), and Na ϩ /Ca 2ϩ transporter (NCX) gene expression and protein. Although SERCA mRNA and protein concentrations did not change with HF, both PLB and NCX were upregulated (P Ͻ 0.05). Additionally, P-PLB and protein kinase A activity were greatly reduced. Allopurinol ameliorated all of these molecular alterations and preserved the PLB-to-SERCA ratio. Preventing maladaptive alterations of Ca 2ϩ cycling proteins represents a novel mechanism for XO inhibition-mediated preservation of cardiac function in HF, raising the possibility that anti-oxidant therapies for HF may ameliorate transcriptional changes associated with adverse cardiac remodeling and -adrenergic hyporesponsiveness. xanthine oxidase; calcium signaling; cardiac contractility and energetics; excitation-contraction coupling; oxidative stress EXCESS REACTIVE OXYGEN SPECIES formation (oxidative stress) contributes to both structural (41) and functional (6, 16) abnormalities in the failing circulation due, at least in part, to upregulated myocardial levels of oxidant-producing enzymes such as xanthine oxidase (XO; see Refs. 5,10,27,39). Allopurinol acutely improves Ca 2ϩ responsiveness of stunned myofilaments (48) and restores cardiac mechanoenergetic coupling, implicating XO-derived oxygen species in both abnormal excitation-contraction (EC) coupling and cardiac energetics (5, 10). XO upregulation also contributes to chronic pathophysiological changes in dysfunctional myocardium resulting from myocardial infarction (MI; see Refs. ...
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