Background-Therapeutic efficacy of bone marrow (BM) cell injection for treating ischemic chronic heart failure has not been established. In addition, experimental data are lacking on arrhythmia occurrence after BM cell injection. We hypothesized that therapeutic efficacy and arrhythmia occurrence induced by BM cell injection may be affected by the cell delivery route. Methods and Results-Three weeks after left coronary artery ligation, wild-type female rats were injected with 1ϫ10

Our data show that the mechanisms of myocardial insulin resistance are different between NIDDM and LVD.

Survival and proliferation of skeletal myoblasts within the cardiac environment are crucial to the therapeutic efficacy of myoblast transplantation to the heart. We have analyzed the early dynamics of myoblasts implanted into the myocardium and investigated the mechanisms underlying graft attrition. At 10 min after implantation of [14C]thymidine-labeled male myoblasts into female mice hearts, 14C measurement showed that 39.2 +/- 3.0% of the grafted cells survived, and this steadily decreased to 16.0 +/- 1.7% by 24 h and to 7.4 +/- 0.9% by 72 h. PCR of male-specific Smcy gene calculated that the total (surviving plus proliferated) number of donor-derived cells was 18.3 +/- 1.6 and 23.3 +/- 1.3% at 24 and 72 h, respectively, indicating that proliferation of the surviving cells began after 24 h. Acute inflammation became prominent by 24 h and was reduced by 72 h as indicated by myeloperoxidase activity and histological findings. Multiplex RT-PCR revealed corresponding changes in IL-1beta, TGF-beta, IL-6, and TNF-alpha expression. Treatment with CuZn-superoxide dismutase attenuated the initial rapid death and resulted in enhanced cell numbers afterward, giving a twofold increased total number at 72 h compared with the nontreatment. This effect was associated with reduced inflammatory response, suggesting a causative role for superoxide in the initial rapid graft death and subsequent inflammation. These data describe the early dynamics of myoblasts implanted into the myocardium and suggest that initial oxidative stress and following inflammatory response may be important mechanisms contributing to acute graft attrition, both of which could be potential therapeutic targets to improve the efficiency of cell transplantation to the heart.

Background-Poor survival of grafted cells is a major factor hindering the therapeutic effect of cell transplantation; however, the causes of cell death remain unclear. We hypothesized that interleukin-1␤ (IL-1␤) might play a role in the acute inflammatory response and graft death after cell transplantation and that inhibition of IL-1␤ might improve graft survival. Methods and Results-14 C-labeled male skeletal muscle precursor cells were implanted into female mouse hearts by direct intramuscular injection. The amount of 14 C-label provides an estimate of the surviving cell number, whereas the amount of male-specific Smcy gene measured by polymerase chain reaction indicates the total (survivingϩproliferated) number of donor-derived cells. At 10 minutes after implantation, 44.8Ϯ2.4% of the grafted cells survived and this steadily decreased to 14.6Ϯ1.1% by 24 hours, and to 7.9Ϯ0.6% by 72 hours (nϭ6 in each point). Proliferation of the surviving cells, which began after 24 hours, resulted in an increase in the total cell number from 15.5Ϯ0.8% at 24 hours to 24.4Ϯ1.6% at 72 hours. Acute inflammation was prominent at 24 hours and was reduced by 72 hours, in parallel with IL-1␤ expression. Administration of anti-IL-1␤ antibody improved graft survival at both 24 (25.6Ϯ1.6%) and 72 hours (14.8Ϯ1.1%) and resulted in a 2-fold increase in the total cell number at 72 hours (45.8Ϯ2.4%). The effects of IL-1␤ inhibition corresponded with a reduced inflammatory response. Conclusion-IL-1␤ is involved in acute inflammation and graft death after direct intramyocardial cell transplantation.Targeted inhibition of IL-1␤ may be a useful strategy to improve graft survival.

Prohibitin (PHB) is a cell cycle regulatory protein, known to repress E2F1-mediated gene activation via recruitment of transcriptional regulatory factors such as retinoblastoma and histone deacetylase 1 (HDAC1). We previously identified PHB as a target protein of androgen signaling in prostate cancer cells and showed that downregulation of PHB is required for androgen-induced cell cycle entry in these cells. We now present evidence that PHB, which has 54% homology at the protein level to the oestrogen receptor corepressor REA (repressor of oestrogen receptor activity), can repress androgen receptor (AR)-mediated transcription and androgen-dependent cell growth. Depletion of endogenous PHB resulted in an increase in expression of the androgen-regulated prostatespecific antigen gene. The repression appears to be specific to androgen and closely related receptors, as it is also evident for the glucocorticoid and progesterone, but not oestrogen, receptors. In spite of interaction of PHB with HDAC1, HDAC activity is not required for this repression. Although AR and PHB could be co-immunoprecipitated, no direct interaction was detectable, suggesting that PHB forms part of a repressive complex with the AR. Competition with the co-activator SRC1 further suggests that formation of a complex with AR, PHB and other cofactors is the mechanism by which repression is achieved. It appears then that repression of AR activity is one mechanism by which PHB inhibits androgendependent growth of prostate cells. Further, this study implies that the AR itself could, by mediating downregulation of a corepressor, be involved in the progression of prostate tumours to the hormone refractory stage.

Background-Intracoronary infusion for cell transplantation has potential advantages in disseminating cells globally into the myocardium with less injury over direct intramuscular injection. Arterial route, however, has a risk of coronary embolism and a limitation in cell delivery into ischemic or infarcted areas. We assessed the efficiency of retrograde intracoronary cell implantation into infarcted hearts using a novel rat model. Methods and Results-After left coronary artery ligation in rat, a catheter was inserted into the left cardiac vein, which drains the left ventricular free wall. Through this, 1ϫ10 6 skeletal muscle precursor cells expressing nuclear ␤-galactosidase were infused retrogradely into the vein. In situ staining demonstrated that ␤-galactosidase-expressing donor cells had disseminated throughout the left ventricular free wall, including both infarcted and surrounding border areas, at 10 minutes after infusion. At 28 days, in contrast, positively stained multinuclear myotubes were found in border zones, whereas no positive cells were seen in infarcted areas. Measurement of ␤-galactosidase enzyme activity estimated that 29.8Ϯ6.9% of total infused cells were retained within the myocardium at 10 minutes and that this number decreased to 23.7Ϯ8.1% at 3 days but rapidly increased thereafter, reaching a plateau at 90.2Ϯ17.1% by 14 days. Echocardiography and Langendorff perfusion demonstrated that cell implantation improved cardiac function and dimensions by 28 days, compared with both sham-treated and phosphate-buffered saline-infused infarcted hearts, and this was associated with decreased collagen deposition. Conclusion-Retrograde intracoronary cell transplantation could provide an effective cell delivery into infarcted hearts and could be a useful strategy for treating myocardial infarction.

In patients with arterial hypertension and left ventricular hypertrophy, perindopril + indapamide reduced blood pressure and left ventricular mass index and improved resting and hyperaemic myocardial blood flow. Data in rats provide evidence that the improvement in coronary flow observed after treatment is due to reverse remodelling of intramural coronary arterioles and improved microvascular function.

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