Elevated Blood Viscosity and Microrecirculation Resulting From Coronary Stent Malapposition.

One particular complexity of coronary artery is the natural tapering of the vessel with proximal segments having larger caliber and distal tapering as the vessel get smaller. The natural tapering of a coronary artery often leads to proximal incomplete stent apposition (ISA). ISA alters coronary hemodynamics and creates pathological path to develop complications such as in-stent restenosis, and more worryingly, stent thrombosis (ST). By employing state-of-the-art computer-aided design software, generic stent hoops were virtually deployed in an idealized tapered coronary artery with decreasing malapposition distance. Pulsatile blood flow simulations were carried out using computational fluid dynamics (CFD) on these computer-aided design models. CFD results reveal unprecedented details in both spatial and temporal development of microrecirculation environments throughout the cardiac cycle (CC). Arterial tapering also introduces secondary microrecirculation. These primary and secondary microrecirculations provoke significant fluctuations in arterial wall shear stress (WSS). There has been a direct correlation with changes in WSS and the development of atherosclerosis. Further, the presence of these microrecirculations influence strongly on the local levels of blood viscosity in the vicinity of the malapposed stent struts. The observation of secondary microrecirculations and changes in blood rheology is believed to complement the wall (-based) shear stress, perhaps providing additional physical explanations for tissue accumulation near ISA detected from high resolution optical coherence tomography (OCT).

Reciprocal regulation of cyclooxygenase 2 and heme oxygenase 1 upon arsenic trioxide exposure in normal human lung fibroblast.

Detoxification enzyme heme oxygenase 1 (HO-1) and proinflammation enzyme cyclooxygenase 2 (Cox-2) are key response proteins that function to promote the survival of cells exposed to arsenic trioxide (ATO). However, whether there is a cross-regulation between them in ATO-treated cells remains poorly investigated. In this study, concomitant upregulation of Cox-2 and HO-1 induced by ATO was observed in normal human lung fibroblasts. Cox-2 inhibitor NS398 suppressed the upregulation of HO-1, whereas HO-1 inhibitor protoporphyrin IX zinc (II) stimulated the expression of Cox-2. Both proteins were regulated by p38, and the feedback regulation of HO-1 on Cox-2 was mediated through p38. Our results confirmed the reciprocal regulations between Cox-2 and HO-1 in ATO-treated normal cells and shed light on the understanding of protecting cells from injury caused by ATO while simultaneously decreasing the inflammation responses, which may be related to the carcinogenicity of ATO.

Mitochondrial transcription factor A regulated ionizing radiation-induced mitochondrial biogenesis in human lung adenocarcinoma A549 cells.

Mitochondrial transcription factor A (TFAM), the first well-characterized transcription factor from vertebrate mitochondria, is closely related to mitochondrial DNA (mtDNA) maintenance and repair. Recent evidence has shown that the ratio of mtDNA to nuclearDNA (nDNA) is increased in both human cells and murine tissues after ionizing radiation (IR). However, the underlying mechanism has not as yet been clearly identified. In the present study, we demonstrated that in human lung adenocarcinoma A549 cells, expression of TFAM was upregulated, together with the increase of the relative mtDNA copy number and cytochrome c oxidase (COX) activity after α-particle irradiation. Furthermore, short hairpin RNA (shRNA)-mediated TFAM knockdown inhibited the enhancement of the relative mtDNA copy number and COX activity caused by α-particles. Taken together, our data suggested that TFAM plays a crucial role in regulating mtDNA amplification and mitochondrial biogenesis under IR conditions.

PFOS-induced apoptosis through mitochondrion-dependent pathway in human-hamster hybrid cells.

Perfluorooctane sulfonate (PFOS) was listed as one of the persistent organic pollutants (POPs) in Stockholm Convention in 2009. Recent evidence showed that PFOS could induce apoptosis both in vivo and in vitro. However, the apoptotic mechanisms induced by PFOS as well as the possible relationship between apoptosis and other PFOS-induced endpoints, remain unclear. In the present study, normal human-hamster hybrid (AL) cells and mtDNA-depleted (ρ(0) AL) cells were exposed to PFOS, and assayed for cytotoxicity, mutagenicity, and apoptosis (caspase-3/7, caspase-9 activities). Our results showed that PFOS decreased cell viability in a time- and concentration-dependent manner in AL cells, but not in ρ(0) AL cells. However, long-term exposure to PFOS failed to induce the mutagenic effects at the CD59 locus in AL cells. Exposure to 200 µM PFOS significantly increased the activities of caspase-3/7 and caspase-9 in AL cells, but the activities of these caspases were not affected in ρ(0) AL cells. In addition, PFOS increased the levels of reactive oxygen species (ROS), superoxide anion (O2(-)), as well as nitric oxide (NO), and decreased mitochondrial membrane potential (MMP) at the concentrations of 100 and 200µM in AL cells. On the other hand, exposure to PFOS had no effect on intracellular ROS, O2(-), and NO production in ρ(0) AL cells. Caspase-3/7 activity, which was increased by 200 µM PFOS, could be suppressed by ROS/O2(-) scavengers and nitric oxide synthases (NOSs) inhibitors in AL cells. These results implicate that PFOS-induced apoptosis and oxidative stress is mediated by a mitochondrion-dependent pathway and that the induction of apoptosis might be a protective function against mutagenesis in AL cells exposed to PFOS.