Concurrent vitamin D supplementation and exercise training improve cardiac fibrosis via TGF-ß/Smad signaling in myocardial infarction model of rats.

Although the role of vitamin D in various types of disorders such as cancer and diabetes has been well recognized, its relation to cardiovascular diseases still remains equivocal. The present study aims to investigate the interactive effects of aerobic-resistance training (ART) and vitamin D3 (VD3) on both cardiac fibrosis and heart functions considering TGF-ß1/Smad2, 3 (transforming growth factor-ß1/mothers against decapentaplegic homolog 2/3) signaling in the myocardial infarction (MI) model of rats. Fifty-six male Wistar rats were divided into 2 groups of sham (n = 8), and MI (n = 48). Then, MI rats were divided into six groups of VD3, ART, VD3+ART, Veh, Veh+ART, and sedentary MI. The animals received the related treatments for 8 weeks, and then their functional exercise capacity (FEC) and strength gain (SG) were estimated through exercise tests. Ejection fraction (EF%) and fractional shortening (FS%) and serum level of VD3 were measured by echocardiography and ELISA, respectively. Cardiac expressions of TGF-ß1, Smad2/3, and collagen I/III were assessed by western blotting and fibrosis by Masson's trichrome staining. The highest EF, parallel with the lowest expression of cardiac TGF-ß1, Smad2/3, collagen I, and collagen III were observed in MI + VD3 (P = 0.021), MI + ART (P = 0.001), and MI + VD3 + ART (P < 0.001). Furthermore, similar to FS, the highest FEC and SG were related to the groups of MI + VD3 + ART and MI + ART compared to the MI group. In conclusion, our data indicate that concurrent vitamin D supplementation and ART, compared with monotherapy, successfully improve cardiac function and alleviate myocardial fibrosis via downregulating TGF-ß1, Smad2/3 signaling, and also regulating collagen I and III expressions.

Comparison of the effects of intramyocardial and intravenous injections of human mesenchymal stem cells on cardiac regeneration after heart failure.

OBJECTIVES: Existing studies have demonstrated that intravenous and intramyocardial-administrated mesenchymal stem cells (MSCs) lead to tissue repair after cardiac disorders. We compared the efficiency of both administration methods. MATERIALS AND METHODS: A rat model of isoproterenol-induced heart failure (ISO-HF) was established to compare the effects of intravenous and intramyocardial-administrated MSCs on cardiac fibrosis and function. The animals were randomly assigned into six groups: i) control or normal, ii) ISO-HF (HF) iii) ISO-HF rats treated with intramyocardial administration of culture medium (HF+IM/CM), iv) ISO-HF rats treated with intravenous administration of culture medium ( HF+IV/CM), v) ISO-HF rats treated with intravenous administration of MSCs (HF+IV/MSCs), vi) ISO-HF rats treated with intramyocardial administration of MSCs ( HF+IM/MSCs). Cultured MSCs and culture medium were administrated at 4 weeks after final injection of ISO. Heart function, identification of MSCs, osteogenic differentiation, adipogenic differentiation, cardiac fibrosis and tissue damage were evaluated by echocardiography, flow-cytometery, von Kossa, oil red O, Masson's trichrome and H & E staining, respectively. RESULTS: Both intravenous and intramyocardial MSCs therapy significantly improved heart function and reduced cardiac fibrosis and tissue damage (P<0.05), whereas the cultured medium had no beneficial effects. CONCLUSION: In sum, our results confirm the validity of both administration methods in recovery of HF, but more future research is required.

Conditioned medium obtained from mesenchymal stem cells attenuates focal cerebral ischemia reperfusion injury through activation of ERK1/ERK2-BDNF signaling pathway.

Previous studies have shown that conditioned medium (CM) obtained from mesenchymal stem cells (MSCs) might exert neuroprotective effects against focal cerebral ischemia reperfusion (I/R) injury. This study was conducted to investigate if CM obtained from MSCs gives rise to neuroprotection by targeting neurogenesis. To induce focal cerebral ischemia in rats, middle cerebral artery (MCA) was occluded for 1 h and the amniotic mesenchymal stem cells-conditioned medium (AMSC-CM) at the dose of 0.5 µl was administered 30 min after reperfusion by stereotactic intracerebral infusion. The animals were randomly divided into three groups: sham operated animals received all procedures except occlusion of MCA (sham, n = 12), I/R group only received occlusion of MCA (MCAO, n = 17), treatment group received MCAO + 0.5 µl of AMSC-CM (MCAO + AMSC-CM, n = 17). The expression of Phospho-ERK1/ERK2, BDNF, VEGF and NGF were determined using immunohistochemical assay. Neuronal loss and DNA fragmentation were evaluated by Nissl and TUNEL assay, respectively. Our results demonstrated that the expression of Phospho-ERK1/ERK2 and BDNF, VEGF and NGF significantly decreased in MCAO rats and was reversed by AMSC-CM. Likewise, AMSC-CM markedly reduced neuronal loss and DNA fragmentation at 24 h after reperfusion. In sum, our study showed that AMSC-CM administration at the onset of reperfusion led to neuroprotection by activating neuronal ERK1/ERK2-BDNF signaling pathway, neurogenesis, angiogenesis as well as suppression of apoptosis.

Improvement of Heart Failure by Human Amniotic Mesenchymal Stromal Cell Transplantation in Rats.

Background: Recently, stem cells have been considered for the treatment of heart diseases, but no marked improvement has been recorded. This is the first study to examine the functional and histological effects of the transplantation of human amniotic mesenchymal stromal cells (hAMSCs) in rats with heart failure (HF). Methods: This study was conducted in the years 2014 and 2015. 35 male Wistar rats were randomly assigned into 5 equal experimental groups (7 rats each) as 1- Control 2- Heart Failure (HF) 3- Sham 4- Culture media 5- Stem Cell Transplantation (SCT). Heart failure was induced using 170 mg/kg/d of isoproterenol subcutaneously injection in 4 consecutive days. The failure confirmed by the rat cardiac echocardiography on day 28. In SCT group, 3×106 cells in 150 µl of culture media were transplanted to the myocardium. At the end, echocardiographic and hemodynamic parameters together with histological evaluation were done. Results: Echocardiography results showed that cardiac ejection fraction in HF group increased from 58/73 ± 9% to 81/25 ± 6/05% in SCT group (p value < 0.001). Fraction shortening in HF group was increased from 27/53 ± 8/58% into 45/55 ± 6/91% in SCT group (p value < 0.001). Furthermore, hAMSCs therapy significantly improved mean diastolic blood pressure, mean arterial pressure, left ventricular systolic pressure, rate pressure product, and left ventricular end-diastolic pressure compared to those in the HF group, with the values reaching the normal levels in the control group. A marked reduction in fibrosis tissue was also found in the SCT group (p value < 0.001) compared with the animals in the HF group. Conclusion: The transplantation of hAMSCs in rats with heart failure not only decreased the level of fibrosis but also conferred significant improvement in heart performance in terms of echocardiographic and hemodynamic parameters.