Losartan Decreases p42/44 MAPK Signaling and Preserves LZ+ MYPT1 Expression

Heart failure is associated with impairment in nitric oxide (NO) mediated vasodilatation, which has been demonstrated to result from a reduction in the relative expression of the leucine zipper positive (LZ+) isoform of the myosin targeting subunit (MYPT1) of myosin light chain phosphatase. Further, captopril preserves normal LZ+ MYPT1 expression, the sensitivity to cGMP-mediated vasodilatation and modulates the expression of genes in the p42/44 MAPK and p38 MAPK signaling cascades. This study tests whether angiotensin receptor blockade (ARB) with losartan decreases p42/44 MAPK or p38 MAPK signaling and preserves LZ+ MYPT1 expression in a rat infarct model of heart failure. In aortic smooth muscle, p42/44 MAPK activation increases and LZ+ MYPT1 expression falls after LAD ligation. Losartan treatment decreases the activation of p42/44 MAPK to the uninfarcted control level and preserves normal LZ+ MYPT1 expression. The expression and activation of p38 MAPK, however, is low and does not change following LAD ligation or with losartan therapy. These data suggest that either reducing or blocking the effects of circulating angiotensin II, both decreases the activation of the p42/44 MAPK signaling cascade and preserves LZ+ MYPT1 expression. Thus, the ability of ACE-inhibitors and ARBs to modulate the vascular phenotype, to preserve normal flow mediated vasodilatation may explain the beneficial effects of these drugs compared to other forms of afterload reduction in the treatment of heart failure

Single Molecule Probing of the Local Segmental Relaxation Dynamics in Polymer above the Glass Transition Temperature

We investigate the temporal dynamics of terrylene diimide molecule with four phenoxy rings (TDI) in a poly(styrene) (PS) matrix in the supercooled regime by use of single molecule spectroscopy. By recording both fluorescence lifetime and linear dichroism observables simultaneously, we show that the TDI dye molecule is a versatile probe of the local dynamics in the polymer. The molecule is able to undergo conformational changes, as indicated by lifetime fluctuations and/or reorientation jumps, as indicated by both observables on different time scales. Owing to molecular mechanics and quantum calculations, we could assign the conformational changes to folding/unfolding event(s) of one or more arms with respect to the conjugated core. We tentatively attribute the different spatial extents of the locally probed motions to the R and beta relaxation processes occurring in the PS matrix