Lack of authentic atrial fibrillation in commonly used murine atrial fibrillation models.

The mouse is a useful preclinical species for evaluating disease etiology due to the availability of a wide variety of genetically modified strains and the ability to perform disease-modifying manipulations. In order to establish an atrial filtration (AF) model in our laboratory, we profiled several commonly used murine AF models. We initially evaluated a pharmacological model of acute carbachol (CCh) treatment plus atrial burst pacing in C57BL/6 mice. In an effort to observe micro-reentrant circuits indicative of authentic AF, we employed optical mapping imaging in isolated mouse hearts. While CCh reduced atrial refractoriness and increased atrial tachyarrhythmia vulnerability, the left atrial (LA) excitation patterns were rather regular without reentrant circuits or wavelets. Therefore, the atrial tachyarrhythmia resembled high frequency atrial flutter, not typical AF per se. We next examined both a chronic angiotensin II (Ang II) infusion model and the surgical model of transverse aortic constriction (TAC), which have both been reported to induce atrial and ventricular structural changes that serve as a substrates for micro-reentrant AF. Although we observed some extent of atrial remodeling such as fibrosis or enlarged LA diameter, burst pacing-induced atrial tachyarrhythmia vulnerability did not differ from control mice in either model. This again suggested that an AF-like pathophysiology is difficult to demonstrate in the mouse. To continue searching for a valid murine AF model, we studied mice with a cardiac-specific deficiency (KO) in liver kinase B1 (Cardiac-LKB1), which has been reported to exhibit spontaneous AF. Indeed, the electrocardiograms (ECG) of conscious Cardiac-LKB1 KO mice exhibited no P waves and had irregular RR intervals, which are characteristics of AF. Histological evaluation of Cardiac-LKB1 KO mice revealed dilated and fibrotic atria, again consistent with AF. However, atrial electrograms and optical mapping revealed that electrical activity was limited to the sino-atrial node area with no electrical conduction into the atrial myocardium beyond. Thus, Cardiac-LKB1 KO mice have severe atrial myopathy or atrial standstill, but not AF. In summary, the atrial tachyarrhythmias we observed in the four murine models were distinct from typical human AF, which often exhibits micro- or macro-reentrant atrial circuits. Our results suggest that the four murine AF models we examined may not reflect human AF well, and raise a cautionary note for use of those murine models to study AF.

Pharmacological profiling of a dual FAK/IGF-1R kinase inhibitor TAE226 in cellular and in vivo tumor models.

OBJECTIVE: A dual inhibitor of focal adhesion kinase (FAK) and insulin-like growth factor 1 receptor (IGF-1R), TAE226, was evaluated in a panel of cancer cell lines, MIA PaCa-2 human pancreatic tumor and 4T1 murine breast tumor models. The profiling data were generated during the drug discovery research prior to the first publication of TAE226 appeared in 2007 (Liu et al. in Mol Cancer Ther 6:1357-1367, 2007; Shi et al. in Mol Carcinog 46(6):488-496, 2007; Halder et al. in Cancer Res 67(22):10976-10983, 2007). RESULTS: In a panel of 37 cancer cell lines, TAE226 showed a mean GI50 value of 0.76 µmol/L. In the MIA PaCa-2 model, TAE226 inhibited phosphorylation of Y397-FAK and phosphorylation of S473-Akt as IGF-1R signaling in the cell culture in vitro and the tumor in mice. Oral administration of TAE226 induced tumor stasis at 30 mg/kg and tumor regression at 100 mg/kg in the subcutaneous tumor, and inhibited the orthotopic tumor growth in a dose-dependent manner. Similarly in the 4T1 model, TAE226 inhibited phosphorylation of Y397-FAK and S473-Akt in the cell culture in vitro and the tumor in mice. Oral administration of TAE226 inhibited the orthotopic tumor growth and metastasis to the lung in a dose-dependent manner. Thus, TAE226 represents a novel class of selective and small molecule kinase inhibitor with a potent in vivo activity.

Accumulation of nerve growth factor protein at both rostral and caudal stumps in the transected rat spinal cord.

Changes in the nerve growth factor (NGF) content in the rat spinal cord during development or after traumatic spinal cord injury were examined by using a two-site enzyme immunoassay (EIA) system and an immunohistochemical technique. From embryonic day (E) 14 to postnatal day (P) 70, the spinal cord contained 200-300 pg NGF/g of wet tissue evenly in all regions tested. After complete spinal cord transection of P49 rats, the NGF level started to increase in the rostral and caudal stumps nearest to the injury site at 2 and 4 days, respectively. The NGF level of the caudal side returned to the original level by 2 weeks, but that of the rostral side remained high even 3 weeks, after the injury. At 4 days after the injury, NGF-like immunoreactivity in both stumps was predominantly localized in the axon-like structures of the white matter and in cells morphologically resembling immune cells. These observations suggest that the NGF was transported within the spinal tracts, and that NGF secreted from immune cells that had invaded into the injured spinal cord had accumulated around the transection site. Increased NGF at the injury site may be advantageous for injured neurons and involved in mechanisms directing to axonal regeneration of the injured spinal cord.

Dependence of electron transfer among alpha cages on the chemical compositions of zeolite LTAs including K clusters.

K atoms are loaded in diluted amount into K-form LTA zeolites whose framework compositions are Al(x)Si(24-x)O(48) (6