Abstract-Myocardial infarction rapidly depletes the endogenous cardiac progenitor cell pool, and the inefficient recruitment of exogenously administered progenitor cells limits the effectiveness of cardiac cell therapy. Recent reports indicate that interactions between the CXC chemokine stromal cell-derived factor 1 and its receptor CXC chemokine receptor 4 (CXCR4) critically mediate the ischemia-induced recruitment of bone marrow-derived circulating stem/progenitor cells, but the expression of CXCR4 in cardiac progenitor cells is very low. Here, we studied the influence of hypoxia on CXCR4 expression in cardiac progenitor cells, on the recruitment of intravenously administered cells to ischemic heart tissue, and on the preservation of heart function in a murine myocardial infarction model. We found that hypoxic preconditioning increased CXCR4 expression in CLK (cardiosphere-derived, Lin Ϫ c-kit ϩ progenitor) cells and markedly augmented CLK cell migration (in vitro) and recruitment (in vivo) to the ischemic myocardium. Four weeks after surgically induced myocardial infarction, infarct size and heart function were significantly better in mice administered hypoxia-preconditioned CLK cells than in mice treated with cells cultured under normoxic conditions. Furthermore, these effects were largely abolished by the addition of a CXCR4 inhibitor, indicating that the benefits of hypoxic preconditioning are mediated by the stromal cell-derived factor 1/CXCR4 axis, and that therapies targeting this axis may enhance cardiac-progenitor cell-based regenerative therapy. Key Words: cardiac progenitor cells Ⅲ hypoxia Ⅲ CXCR4 Ⅲ cell migration Ⅲ myocardial infarction I schemic heart disease and consequent heart failure remain the leading cause of morbidity and mortality worldwide. 1 Traditional therapies, such as angioplasty and thrombolytic agents, can relieve only the cause of infarction; no existing medication or procedure can effectively replace cardiac scarring with functional contractile tissue. However, newer therapies that incorporate recently identified populations of progenitor cells may regenerate cardiac tissue directly by inducing neovasculogenesis and cardiogenesis. [2][3][4][5][6][7][8][9][10] Resident cardiac progenitor cells may be particularly suitable for resurrecting dead myocardium because they are endogenous components of the adult heart and appear to be responsible for the physiological and pathological turnover of cardiac myocytes and other cardiac cells. 11 Cardiac progenitor cells are self-renewing, clonogenic, and multipotent, giving rise to myocytes, vascular smooth muscle cells, endothelial cells, and neural crest cells. 2,6,12 Although cardiac progenitor cells may seem to be the obvious choice for cell-based cardiac repair, the success of this approach is determined, in part, by the same factors that cause the endogenous cardiac repair system to fail. Within a day of myocardial infarction (MI), 40% of resident cardiac progenitor cells are depleted, 8 and the barriers imposed by cardiac damage may ...

A hypoxia-regulated HO-1 vector modification of MSCs enhances the tolerance of engrafted MSCs to hypoxia-reoxygen injury in vitro and improves their viability in ischemic hearts. This demonstration is the first showing that a physiologically inducible vector expressing of HO-1 genes improves the survival of stem cells in myocardial ischemia.

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A brain renin angiotensin system (RAS) and its role in cardiovascular control and fluid homeostasis was at first controversial. This was because a circulating kidney-derived renin angiotensin system was so similar and well established. But, the pursuit of brain RAS has proven to be correct. In the course of accepting brain RAS, high standards of proof attracted state of the art techniques in all the new developments of biology. Consequently, brain RAS is a robust concept that has enlightened neuroscience as well as cardiovascular physiology and is a model neuropeptide system. Molecular biology confirmed the components of brain RAS and their location in the brain. Transgenic mice and rats bearing renin and extra copies of angiotensinogen genes revealed the importance of brain RAS. Cre-lox delivery in vectors has enabled pinpoint gene deletion of brain RAS in discrete brain nuclei. The new concept of brain RAS includes ACE-2, Ang1-7, and prorenin and Mas receptors. Angiotensin II (ANG II) generated in the brain by brain renin has many neural effects. It activates behavioral effects by selective activation of ANG II receptor subtypes in different locations. It regulates sympathetic activity and baroreflexes and contributes to neurogenic hypertension. New findings implicate brain RAS in a much wider range of neural effects. We review brain RAS involvement in Alzheimer's disease, stroke memory, and learning alcoholism stress depression. There is growing evidence to consider developing treatment strategies for a variety of neurological disease states based on brain RAS.