Cellular cardiomyoplasty: what have we learned?

Restoring blood flow, improving perfusion, reducing clinical symptoms, and augmenting ventricular function are the goals after acute myocardial infarction. Other than cardiac transplantation, no standard clinical procedure is available to restore damaged myocardium. Since we first reported cellular cardiomyoplasty in 1989, successful outcomes have been confirmed by experimental and clinical studies, but definitive long-term efficacy requires large-scale placebo-controlled double-blind randomized trials.

Preconditioning with a TLR2 specific ligand increases resistance to cerebral ischemia/reperfusion injury.

The brain's resistance to ischemic injury can be transiently augmented by prior exposure to a sub-lethal stress stimulus, i.e. preconditioning.

Lipopolysaccharide-induced myocardial protection against ischaemia/reperfusion injury is mediated through a PI3K/Akt-dependent mechanism.

Aims: The ability of lipopolysaccharide (LPS) pre-treatment to induce cardioprotection following ischaemia/reperfusion (I/R) has been well documented; however, the mechanisms have not been fully elucidated. LPS is a Toll-like receptor 4 (TLR4) ligand. Recent evidence indicates that there is cross-talk between the TLR and phosphoinositide 3-kinase/Akt (PI3K/Akt) signalling pathways.

Activation of Toll-like receptor 4 signaling contributes to hippocampal neuronal death following global cerebral ischemia/reperfusion.

Toll-like receptors (TLRs) play a critical role in the induction of innate immune responses which have been implicated in neuronal death induced by global cerebral ischemia/reperfusion (GCI/R). The present study investigated the role and mechanisms-of-action of TLR4 signaling in ischemia-induced hippocampal neuronal death. Neuronal damage, activation of the TLR4 signaling pathway, expression of pro-inflammatory cytokines and activation of the PI3K/Akt signaling pathway in the hippocampal formation (HF) were assessed in wild type (WT) mice and TLR4 knockout (TLR4(-/-)) mice after GCI/R.

Protection against myocardial ischemia/reperfusion injury in TLR4-deficient mice is mediated through a phosphoinositide 3-kinase-dependent mechanism.

TLRs play a critical role in the induction of innate and adaptive immunity. However, TLRs have also been reported to mediate the pathophysiology of organ damage following ischemia/reperfusion (I/R) injury. We have reported that TLR4(-/-) mice show decreased myocardial injury following I/R; however, the protective mechanisms have not been elucidated.

Glucan phosphate attenuates cardiac dysfunction and inhibits cardiac MIF expression and apoptosis in septic mice.

Myocardial dysfunction is a major consequence of septic shock and contributes to the high mortality of sepsis. We have previously reported that glucan phosphate (GP) significantly increased survival in a murine model of cecal ligation and puncture (CLP)-induced sepsis. In the present study, we examined the effect of GP on cardiac dysfunction in CLP-induced septic mice.

The development of a novel mouse model of transient global cerebral ischemia.

A reproducible model of global cerebral ischemia in mice is essential for elucidating the molecular mechanism(s) of neuronal damage induced by cerebral ischemia/reperfusion injury. In the present study, we developed a mouse model of transient global ischemia induced by occlusion of the bilateral common carotid arteries and the left subclavian artery together with right subclavian artery (RSA) stenosis (CSOSS) under controlled ventilation in C57BL/10ScSn mice. The mean arterial blood pressure was maintained in the physiological range.

Attenuation of cardiac hypertrophy by inhibiting both mTOR and NFkappaB activation in vivo.

A role for the PI3K/Akt/mTOR pathway in cardiac hypertrophy has been well documented. We reported that NFkappaB activation is needed for cardiac hypertrophy in vivo. To investigate whether both NFkappaB activation and PI3K/Akt/mTOR signaling participate in the development of cardiac hypertrophy, two models of cardiac hypertrophy, namely, induction in caAkt-transgenic mice and by aortic banding in mice, were employed.

Blocking the MyD88-dependent pathway protects the myocardium from ischemia/reperfusion injury in rat hearts.

We examined whether blocking the MyD88 mediated pathway could protect myocardium from ischemia/reperfusion (I/R) injury by transfecting Ad5-dnMyD88 into the myocardium of rats (n=8) 3 days before the hearts were subjected to ischemia (45min) and reperfusion (4h). Ad5-GFP served as control (n=8). One group of rats was (n=8) subjected to I/R without transfection.

Overexpression of TLR2 and TLR4 susceptibility to serum deprivation-induced apoptosis in CHO cells.

We examined the effect of overexpression of TLR2 and TLR4 on apoptosis. TLR2 and TLR4 transfected CHO cells were subjected to serum deprivation for 0, 24, and 48 h. CHO cells served as control.

Blockade of MyD88 attenuates cardiac hypertrophy and decreases cardiac myocyte apoptosis in pressure overload-induced cardiac hypertrophy in vivo.

In this study, we evaluated whether blocking myeloid differentiation factor-88 (MyD88) could decrease cardiac myocyte apoptosis following pressure overload. Adenovirus expressing dominant negative MyD88 (Ad5-dnMyD88) or Ad5-green fluorescent protein (GFP) (Ad5-GFP) was transfected into rat hearts (n = 8/group) immediately followed by aortic banding for 3 wk. One group of rats (n = 8) was subjected to aortic banding for 3 wk without transfection.

Reduced cardiac hypertrophy in toll-like receptor 4-deficient mice following pressure overload.

Objective: We have previously demonstrated that nuclear factor kappa B (NFkappaB) activation is needed for the development of cardiac hypertrophy in vivo. NFkappaB is a downstream transcription factor in the Toll-like receptor (TLR)-mediated signaling pathway; therefore, we investigated a role of TLR4 in cardiac hypertrophy in vivo.

Methods: TLR4-deficient mice (C.

At low serum glucan concentrations there is an inverse correlation between serum glucan and serum cytokine levels in ICU patients with infections.

Glucans are fungal cell wall glucose polymers that are released into the blood of infected patients. The role of glucans in infection is unknown. We examined serum glucan and cytokine levels in intensive care unit (ICU) patients with infections.

NF-kappaB activation is required for the development of cardiac hypertrophy in vivo.

In the present study, we examined whether NF-kappaB activation is required for cardiac hypertrophy in vivo. Cardiac hypertrophy in rats was induced by aortic banding for 1, 3, and 5 days and 1-6 wk, and age-matched sham-operated rats served as controls. In a separate group of rats, an IkappaB-alpha dominant negative mutant (IkappaB-alphaM), a superrepressor of NF-kappaB activation, or pyrrolidinedithiocarbamate (PDTC), an antioxidant that can inhibit NF-kappaB activation, was administered to aortic-banded rats for 3 wk.

Modulating Toll-like receptor mediated signaling by (1-->3)-beta-D-glucan rapidly induces cardioprotection.

Objective: Immune and inflammatory signaling pathways, initiated by the innate response, are involved in myocardial ischemia/reperfusion (I/R) injury. Toll-like receptor (TLR) mediated MyD88-dependent NFkappaB pathways play a role in the induction of innate immunity. We have reported that glucan phosphate (GP) improved survival in experimental sepsis, which correlated with decreased tissue NFkappaB activation.

Serum glucan levels are not specific for presence of fungal infections in intensive care unit patients.

Fungal infections in the critically ill patient are difficult to diagnose and are associated with a high mortality rate. A major obstacle to managing fungal infection is the lack of a reliable clinical assay that will rapidly identify patients with fungal sepsis. Glucans are polymers of glucose that are found in the cell wall of fungi and certain bacteria.

Modulation of tissue Toll-like receptor 2 and 4 during the early phases of polymicrobial sepsis correlates with mortality.

Objective: To determine whether there was a correlation between induction of polymicrobial sepsis, modulation of tissue Toll-like receptor (TLR) gene, and protein expression and survival outcome.

Design: Prospective, randomized animal study.

Setting: University medical school research laboratory.

Primary aortogastric fistula after nissen fundoplication: a case report and review of pertinent literature.

Aortogastric fistulas are a rare but usually fatal entity that presents as an acute gastrointestinal bleeding. The authors present the case of a 65-year-old man who had undergone a Nissen fundoplication and presented in the emergency room with syncope secondary to massive upper gastrointestinal tract bleed. Despite aggressive resuscitation and prompt operative intervention with repair of the gastric ulcer and closure of the aortic side of the fistula, he succumbed to the complications of hypovolemic shock.

Activation of AP-1 and SP1 correlates with wound growth factor gene expression in glucan-treated human fibroblasts.

Glucan is a natural product immunomodulator that has been reported to enhance early wound repair. The mechanism of glucan-stimulated wound repair was thought to be indirect via macrophage release of wound growth factors. However, recent data indicate that there are glucan-specific receptors on human fibroblasts that can modulate cellular function following interaction with the glucan ligand.

Human monocyte scavenger receptors are pattern recognition receptors for (1-->3)-beta-D-glucans.

Glucans are cell wall constituents of fungi and bacteria that bind to pattern recognition receptors and modulate innate immunity, in part, by macrophage activation. We used surface plasmon resonance to examine the binding of glucans, differing in fine structure and charge density, to scavenger receptors on membranes isolated from human monocyte U937 cells. Experiments were performed at 25 degrees C using a biosensor surface with immobilized acetylated low density lipoprotein (AcLDL).

Glucan stimulates human dermal fibroblast collagen biosynthesis through a nuclear factor-1 dependent mechanism.

Glucan, an immunomodulator, has been reported to increase collagen deposition and tensile strength in experimental models of wound repair. Previous data suggest that glucan modulates wound healing via an indirect mechanism in which macrophages are stimulated to release growth factors and cytokines. However, recent data have shown the presence of glucan receptors on normal human dermal fibroblasts, suggesting that glucans may be able to directly stimulate fibroblast collagen biosynthesis.

Human vascular endothelial cells express pattern recognition receptors for fungal glucans which stimulates nuclear factor kappaB activation and interleukin 8 production. Winner of the Best Paper Award from the Gold Medal Forum.

Fungal cell wall glucans nonspecifically stimulate various aspects of innate immunity via interaction with membrane receptors on macrophages, neutrophils, and natural killer cells. We investigated the binding of water-soluble glucans in primary cultures of normal human coronary or dermal vascular endothelial cells (VECs). Membranes from VECs exhibited saturable binding.