Abstract. The angiotensin (Ang) II/Ang II receptor (ATR)-associated calcium signaling pathway is the major cause of ventricular remodelling in patients with congestive heart failure (CHF). However, the calcium-regulated proteinases responsible for Ang II-induced remodelling are not well understood. We investigated the profiles of the Ang II/ ATR/calpain/calcineurin (CaN) pathway in human failing heart. We measured both the plasma and cardiac levels of Ang II and cardiac mRNA expression of ATR in 39 patients with CHF and 38 healthy controls. Importantly, protein expression of calpains, cleavage of cain/cabin1 and activity of CaN were tested. Both plasma and cardiac levels of Ang II were significantly increased in patients with CHF (both p<0.01), and the plasma Ang II concentration was closely correlated with the parameters of ventricular remodelling (r=±0.29-0.65, p<0.05 or <0.01). In addition, the cardiac level of AT1R but not AT2R was significantly upregulated in mild failing hearts (p<0.05) but dramatically downregulated in severe failing ones (p<0.01). CHF was associated with a marked upregulation of calpains, an increased cleavage of cain/cabin1, and the activation of CaN in the failing ventricular tissue. In patients with CHF, calpain upregulation was associated with an increase in cleavage of cain/cabin1 and the activation of CaN, indicating that these changes in calciumregulated proteinases contribute to Ang II-induced cardiac remodelling.

Transplantation of stem cells, including mesenchymal stromal cells (MSCs), improves the recovery of cardiac function after myocardial infarction (MI) in experimental studies using animal models and in patients. However, the improvement of cardiac function following MSC transplantation remains suboptimal in both preclinical and clinical studies. Understanding the mechanism of cell therapy may improve its therapeutic outcomes, but the mode of action mediating stem cell promotion of cardiac repair is complex and not fully understood. Recent studies suggest that the immunomodulatory effects of MSCs on the macrophage M1/M2 subtype transition allow the transplanted stem cells to inhibit inflammation-induced injury and promote cardiac repair in acute MI. However, equally compelling evidence shows that there is poor survival and minimal graft persistence of transplanted MSCs within the infarcted heart tissues, negating the view that graft survival per se is required for the observed high rate and long duration of the transition from proinflammatory M1 to reparative M2 macrophages in the infarcted myocardium. Therefore, we raised a novel hypothesis that the therapeutic effects of MSC transplantation for acute MI depends not primarily on the grafted cells in infarct myocardium, but that MSCs migrating to and being lodged in the extracardiac organs, demonstrating good graft survival and persistence, may render the therapeutic effects in MI. More specifically, MSC transplantation promotes the transition from M1 to M2 in extracardiac organs, such as spleen and bone marrow, and therapeutic effects are conferred to the infarcted myocardium via paracrine effects. In MSC transplantation, the conversion from proinflammatory M1 to anti-inflammatory M2 monocytes may occur remotely from the heart and may serve as one of the major pathways in regulating the dual effects of inflammation. This hypothesis, if proven valid, may represent an important new mechanism of action to be considered for the future of MSC transplantation in the treatment of MI.

No abstract

The present study demonstrated that diabetes increased restenosis after sirolimus-eluting stent placement in STEMI patients. This finding implicates that diabetes remains an important predictor for restenosis in the DES era.

Abstract. Basic transcription element-binding protein 2 (BTeB2) is a regulator of the proliferation and phenotypic changes of vascular smooth muscle cells (SMcs). The aim of the present study was to determine whether or not BTeB2 knockdown inhibits balloon injury-induced neointimal hyperplasia attributed to the proliferation and phenotypic changes of vascular SMcs. We found that the knockdown of BTeB2 with antisense oligonucleotides (Ad-As-BTEB2) significantly reduced the intima/media ratio compared to uninjured arteries and vessels treated with ad-lacZ. Knockdown of BTeB2 suppresses the proliferation of cultured vascular SMcs, concurrent with the down-regulation of proliferating cell nuclear antigen, angiotensin ii type 1 receptor and plateletderived growth factor BB. in addition, BTeB2 knockdown caused the up-regulation of the differentiation marker smooth muscle α-actin and down-regulation of the dedifferentiation marker embryonic smooth muscle myosin heavy chain. The present study provides direct evidence that BTeB2 plays a critical role in balloon injury-induced neointimal hyperplasia, which is closely linked to vascular SMc proliferation and phenotypic modulation. This study highlights the fact that BTeB2 may be a potential target for the prevention of restenosis after vascular intervention.