Myocyte-Specific Overexpressing HDAC4 Promotes Myocardial Ischemia/Reperfusion Injury

Background: Histone deacetylases (HDACs) play a critical role in modulating myocardial protection and cardiomyocyte survivals. However, Specific HDAC isoforms in mediating myocardial ischemia/reperfusion injury remain currently unknown. We used cardiomyocyte-specific overexpression of active HDAC4 to determine the functional role of activated HDAC4 in regulating myocardial ischemia and reperfusion in isovolumetric perfused hearts. Methods: In this study, we created myocyte-specific active HDAC4 transgenic mice to examine the functional role of active HDAC4 in mediating myocardial I/R injury. Ventricular function was determined in the isovolumetric heart, and infarct size was determined using tetrazolium chloride staining. Results: Myocyte-specific overexpressing activated HDAC4 in mice promoted myocardial I/R injury, as indicated by the increases in infarct size and reduction of ventricular functional recovery following I/R injury. Notably, active HDAC4 overexpression led to an increase in LC-3 and active caspase 3 and decrease in SOD-1 in myocardium. Delivery of chemical HDAC inhibitor attenuated the detrimental effects of active HDAC4 on I/R injury, revealing the pivotal role of active HDAC4 in response to myocardial I/R injury. Conclusions: Taken together, these findings are the first to define that activated HDAC4 as a crucial regulator for myocardial ischemia and reperfusion injury

Activation of Myocardial Phosphoinositide-3-Kinase p110α Ameliorates Cardiac Dysfunction and Improves Survival in Polymicrobial Sepsis

Phosphoinositide-3-kinase (PI3K)/Akt dependent signaling has been shown to improve outcome in sepsis/septic shock. There is also ample evidence that PI3K/Akt dependent signaling plays a crucial role in maintaining normal cardiac function. We hypothesized that PI3K/Akt signaling may ameliorate septic shock by attenuating sepsis-induced cardiac dysfunction. Cardiac function and survival were evaluated in transgenic mice with cardiac myocyte specific expression of constitutively active PI3K isoform, p110α (caPI3K Tg). caPI3K Tg and wild type (WT) mice were subjected to cecal ligation/puncture (CLP) induced sepsis. Wild type CLP mice showed dramatic cardiac dysfunction at 6 hrs. Septic cardiomyopathy was significantly attenuated in caPI3K CLP mice. The time to 100% mortality was 46 hrs in WT CLP mice. In contrast, 80% of the caPI3K mice survived at 46 hrs after CLP (p30 days (

Use of a preclinical test in the control of classical scrapie

Scrapie control in Great Britain (GB) was originally based on the National Scrapie Plan's Ram Genotyping scheme aimed at reducing the susceptibility of the national flock. The current official strategy to control scrapie in the national flock involves culling susceptible genotypes in individual, known affected flocks (compulsory scrapie flock scheme or CSFS). However, the recent development of preclinical test candidates means that a strategy based on disease detection may now be feasible. Here, a deterministic within-flock model was used to demonstrate that only large flocks with many home-bred ewes are likely to be a significant risk for flock-to-flock transmission of scrapie. For most other flocks, it was found that the CSFS could be replaced by a strategy using a currently available live test without excessive risk to other farmers, even if the proportion of susceptible genotypes in the flock is unusually large. Even for flocks that represent a high risk of harbouring a high prevalence of infection, there would be limited probability of onward transmission if scrapie is detected soon after disease introduction (typically less than 5 years). However, if detection of disease is delayed, the existing CSFS strategy may be the most appropriate control measure in these cases

Dengue: a continuing global threat.

Dengue fever and dengue haemorrhagic fever are important arthropod-borne viral diseases. Each year, there are ∼50 million dengue infections and ∼500,000 individuals are hospitalized with dengue haemorrhagic fever, mainly in Southeast Asia, the Pacific and the Americas. Illness is produced by any of the four dengue virus serotypes. A global strategy aimed at increasing the capacity for surveillance and outbreak response, changing behaviours and reducing the disease burden using integrated vector management in conjunction with early and accurate diagnosis has been advocated. Antiviral drugs and vaccines that are currently under development could also make an important contribution to dengue control in the future

Cellular Cardiomyoplasty: Its Past, Present, and Future

Cellular cardiomyoplasty is a cell therapy using stem cells or progenitor cells for myocardial regeneration to improve cardiac function and mitigate heart failure. Since we first published cellular cardiomyoplasty in 1989, this procedure became the innovative method to treat damaged myocardium other than heart transplantation. A significant improvement in cardiac function, metabolism, and perfusion is generally observed in experimental and clinical studies, but the improvement is mild and incomplete. Although safety, feasibility, and efficacy have been well documented for the procedure, the beneficial mechanisms remain unclear and optimization of the procedure requires further study. This chapter briefly reviews the stem cells used for cellular cardiomyoplasty and their clinical outcomes with possible improvements in future studies

Skeletal Muscle Stem Cells

Skeletal muscle satellite cells (myoblasts) are the primary stem cells of skeletal muscle which contribute to growth, maintenance, and repair of the muscles. Satellite cells are the first stem cells used for cellular cardiomyoplasty more than 20 years ago. The isolation, culture, labeling, and identification of satellite cells are described in detail here. The implantation and outcomes of cellular cardiomyoplasty using satellite cells have been summarized in the previous chapter (Chapter 1)

Microvasculature of the Urinary Bladder of the Dog: A Study Using Vascular Corrosion Casting

The urinary bladder is an unusual organ in that its normal function includes filling and emptying with alternating changes in internal pressure. Although fluctuations in blood flow to the bladder wall are known to accompany these changes, detailed descriptions of the bladder microvasculature are sparse. The present study uses vascular corrosion casting and scanning electron microscopy to describe the three-dimensional anatomy of the microvasculature of the urinary bladder of the dog. Specialized features of that microvasculature, including collateral circulation, vessel folding, vessel orientation, the presence of valves and sphincters, and mucosal capillary density, that may enhance and control blood flow during normal bladder function, are described and discussed

Early Activation of Transcription Factor NF-κB During Ischemia in Perfused Rat Heart

The transcription factor nuclear factor κB (NF-κB) regulates multiple immediate-early gene expressions involved in immune and inflammatory responses and cellular defenses. Ischemia-reperfusion induces many immediate- early gene expressions, but little is known about the NF-κB activation in myocardium during ischemia and reperfusion. This study demonstrated that ischemia alone rapidly induced NF-κB activation in the myocardium of isolated working rat hearts. Electrophoretic mobility shift assay showed that NF-κB binding activity significantly increased in the nucleus after 5 min of ischemia and remained elevated for up to 30 min. Western blot analysis suggested that the levels of inhibitory IκBα protein in the cytoplasm became markedly decreased at 4, 5, 7.5, and 10 min of ischemia but were gradually restored following 10 min of ischemia. Reduction of IκBα protein in the cytoplasm by ischemia resulted in NF-κB translocation to the nucleus. Northern blot hybridization showed that IκBα mRNA levels were not significantly elevated during myocardial ischemia. Pyrrolidine dithiocarbamate, an antioxidant, significantly inhibited the loss of IκBα protein from the cytoplasm and prevented NF-κB binding activity in the nucleus. Reperfusion following short periods of ischemia augmented NF-κB binding activity in the nucleus induced by ischemia. The results suggest that early activation of NF-κB induced by ischemia in the myocardium could be a signal mechanism for controlling and regulating immediate-early gene expression during ischemia-reperfusion