Intracellular and Extracellular Effects of S100B in the Cardiovascular Response to Disease

S100B, a calcium-binding protein of the EF-hand type, exerts both intracellular and extracellular functions. S100B is induced in the myocardium of human subjects and an experimental rat model following myocardial infarction. Forced expression of S100B in neonatal rat myocyte cultures and high level expression of S100B in transgenic mice hearts inhibit cardiac hypertrophy and the associated phenotype but augments myocyte apoptosis following myocardial infarction. By contrast, knocking out S100B, augments hypertrophy, decreases apoptosis and preserves cardiac function following myocardial infarction. Expression of S100B in aortic smooth muscle cells inhibits cell proliferation and the vascular response to adrenergic stimulation. S100B induces apoptosis by an extracellular mechanism via interaction with the receptor for advanced glycation end products and activating ERK1/2 and p53 signaling. The intracellular and extracellular roles of S100B are attractive therapeutic targets for the treatment of both cardiac and vascular diseases

DJ-1 Deficiency Protects against Sepsis-Induced Myocardial Depression

Oxidative stress is considered one of the early underlying contributors of sepsis-induced myocardial depression. DJ-1, also known as PARK7, has a well-established role as an antioxidant. We have previously shown, in a clinically relevant model of polymicrobial sepsis, DJ-1 deficiency improved survival and bacterial clearance by decreasing ROS production. In the present study, we investigated the role of DJ-1 in sepsis-induced myocardial depression. Here we compared wildtype (WT) with DJ-1 deficient mice at 24 and 48 h after cecal ligation and puncture (CLP). In WT mice, DJ-1 was increased in the myocardium post-CLP. DJ-1 deficient mice, despite enhanced inflammatory and oxidative responses, had an attenuated hypertrophic phenotype, less apoptosis, improved mitochondrial function, and autophagy, that was associated with preservation of myocardial function and improved survival compared to WT mice post-CLP. Collectively, these results identify DJ-1 as a regulator of myocardial function and as such, makes it an attractive therapeutic target in the treatment of early sepsis-induced myocardial depression

Improved post-myocardial infarction survival with probucol in rats: Effects on left ventricular function, morphology, cardiac oxidative stress and cytokine expression

AbstractObjectivesThe goal of this study was to evaluate whether reducing the potentially deleterious effects of oxidative stress with the potent anti-oxidant probucol improves prognosis after myocardial infarction (MI) in rats.BackgroundOxidative stress has been documented in patients early and late after MI, particularly when it is associated with congestive heart failure.MethodsRats surviving acute MIs for 24 h (n = 247) were assigned to vehicle or probucol (61 mg/kg, daily) for four weeks, at which time cardiac hemodynamic, morphologic and molecular measurements were done.ResultsIn rats with large MIs, probucol improved survival (87.9%) when compared with vehicle (50.6%) (p < 0.001). Probucol also partially preserved left ventricular (LV) systolic but not diastolic function. Probucol increased scar thickness and decreased cardiac fibrosis but did not modify LV hypertrophy or dilation. Finally, probucol decreased cardiac oxidative stress, as assessed by measuring cardiac malondialdehydes, and decreased the cardiac expression of the pro-inflammatory cytokines interleukin (IL)-1β and IL-6 but did not modify fetal gene re-expression in rats with large MIs.ConclusionsThis study indicates that the anti-oxidant probucol markedly improves post-MI survival in rats despite few demonstrable effects on cardiac remodeling or hemodynamics. Its beneficial effects may, however, be associated with reduced cardiac fibrosis, oxidative stress and expression of pro-inflammatory cytokines

Donor Mesenchymal Stromal Cells (MSCs) Undergo Variable Cardiac Reprogramming in Vivo and Predominantly Co-Express Cardiac and Stromal Determinants after Experimental Acute Myocardial Infarction

We previously showed the emergence of predominantly non-fused murine cells co-expressing cardiac and stromal determinants in co-cultures of murine mesenchymal stromal cells (MSCs) and rat embryonic cardiomyocytes. To determine whether a similar phenotype is detectable in vivo in ischemic myocardium, we infused green fluorescence protein (GFP)-marked MSCs intravenously into wild-type mice in an acute myocardial infarction (AMI) model generated by ischemia/reperfusion (I/R) or fixed coronary artery ligation. We found that infused GFP+ cells were confined strictly to ischemic areas and represented approximately 10% of total cellularity. We showed that over 60% of the cells co-expressed collagen type IV and troponin T or myosin heavy chain, characteristic of MSCs and cardiomyocytes, respectively, and were CD45(-). Nonetheless, up to 25% of the GFP+ donor cells expressed one of two cardiomyocyte markers, either myosin heavy chain or troponin T, in the absence of MSC determinants. We also observed a marked reduction in OCT4 expression in MSCs pre-infusion compared with those lodged in the myocardium, suggesting reduced stem cell properties. Despite the low frequency of lodged donor MSCs, left-ventricular end-diastolic pressure was significantly better in experimental versus saline animals for both AMI (12.10±1.81 vs. 20.50±1.53 mmHg, p=0.001) and I/R models (8.75±2.95 vs. 17.53±3.85 mmHg, p=0.004) when measured 21 days after MSC infusion and is consistent with a paracrine effect. Our data indicate that donor MSCs undergo variable degrees of cardiomyocyte reprogramming with the majority co-expressing cardiomyocyte and stromal markers. Further studies are needed to elucidate the factors mediating the extent of cardiomyocyte reprogramming and importance of the cellular changes on tissue repair.Fil: Yannarelli, Gustavo Gabriel. University of Toronto; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Tsoporis, James N.. St. Michael’s Hospital. Li Ka Shing Knowledge Institute. Keenan Research Centre. Department of Medicine. Division of Cardiology; CanadáFil: Desjardins, Jean Francois. St. Michael’s Hospital. Li Ka Shing Knowledge Institute. Keenan Research Centre. Department of Medicine. Division of Cardiology; CanadáFil: Wang, Xing Hua. University of Toronto; CanadáFil: Pourdjabbar, Ali. St. Michael’s Hospital. Li Ka Shing Knowledge Institute. Keenan Research Centre. Department of Medicine. Division of Cardiology; CanadáFil: Viswanathan, Sowmya. University of Toronto; CanadáFil: Parker, Thomas G.. St. Michael’s Hospital. Li Ka Shing Knowledge Institute. Keenan Research Centre. Department of Medicine. Division of Cardiology; CanadáFil: Keating, Armand. University of Toronto; Canad