The mechanism of nickel-catalyzed couplings of an enone, alkyne, and organozinc has been studied. Adducts of the substrates with nickel(0) have been isolated and characterized, and their reactivity was examined. A potential intermediate was demonstrated to not be kinetically competent in catalytic cyclizations. A computational approach employing the B3LYP density functional method and the 6-31G(d) basis set was used to examine mechanistic possibilities that were consistent with experimental observations, and a modified mechanism for the catalytic cyclizations was formulated. The newly proposed mechanism involves production of an active catalyst that involves a novel interaction between Ni(0) and dimethylzinc.

Background Hypertension or aortic stenosis causes pressure overload, which evokes hypertrophic myocardial growth. Sustained cardiac hypertrophy eventually progresses to heart failure. Growing evidence indicates that restraining hypertrophy could be beneficial; here we discovered that FTY-720, an immuno-modulator for treating multiple sclerosis, can reverse existing cardiac hypertrophy/fibrosis. Methods and Results Male C57/Bl6 mice underwent transverse aortic constriction (TAC) for 1 week followed by FTY-720 treatment for 2 weeks under continuing TAC. Compared to vehicle-treated TAC hearts, FTY-720 significantly reduced ventricular mass, ameliorated fibrosis and improved cardiac performance. Mechanistic studies led us to discover that FTY-720 appreciably inhibited NFAT activity. Moreover, we found that in primary cardiomyocytes (rat and human) pertussis toxin (PTX, Gi-coupled receptor inhibitor) substantially blocked the anti-hypertrophic effect of FTY-720. This observation was confirmed in a mouse model of pressure overload. Interestingly, gene array analysis of TAC-hearts revealed that FTY-720 profoundly decreased gene expression of a group of matricellular proteins, of which periostin was prominent. Analysis of periostin protein expression in TAC-myocardium, as well as in rat and human cardiac fibroblasts confirmed the array data. Moreover, we found that FTY-720 treatment or knockdown of periostin protein was able to inhibit TGF-β responsiveness and decrease collagen expression. Conclusions FTY-720 alleviates existing cardiac hypertrophy/fibrosis through mechanisms involving negative regulation of NFAT activity in cardiomyocytes and reduction of periostin expression allowing for a more homeostatic extracellular compartment milieu. Together, FTY-720 or its analogues could be a promising new approach for treating hypertrophic/fibrotic heart disease.

Two metallacycles derived from the oxidative cyclization of nickel(0) with an alkynyl enal have been isolated and fully characterized. The metallacycles obtained possess an η 1 nickel O-enolate motif within the metallacyclic framework.

Mitogen-activated protein kinases (MAPKs) are involved in the regulation of cardiac hypertrophy and myocyte survival. Extracellular signal regulated protein kinase 1 and 2 (ERK1/2) are key components in the MAPK signaling pathways. Dysfunction of ERK1/2 in congenital heart diseases (Noonan syndrome and LEOPARD syndrome) leads to cardiac hypertrophy. ERK2 contributes 70% of protein content to total ERK1/2 content in myocardium; however, the specific role of ERK2 in regulating cardiac hypertrophy is yet to be further defined.To investigate the specific role of ERK2 played in the cardiomyocytes, we generated and examined mice with cardiomyocyte-specific deletion of the erk2 gene (ERK2cko mice). Following short-term pathological hypertrophic stresses, the mutant mice showed attenuated hypertrophic remodeling characterized by a blunted increase in the cross-sectional area of individual myocytes, downregulation of hypertrophic foetal gene markers (ANP and BNP), and less interstitial fibrosis. However, increased cardiomyocyte apoptosis was observed. Upon prolonged stimulation, ERK2cko mice developed deterioration in cardiac function. However, absence of ERK2 did not affect physiological hypertrophy induced by 4 weeks of swimming exercise.These results revealed an essential role for ERK2 in cardiomyocytes in the development of pathological hypertrophic remodeling and resistance to cell death.