We examined the role of p38α MAPK in mediating cardiomyopathy in mice overexpressing β 1 -adrenergic receptor (β 1 -AR) or β 2 -AR by mating them with dominant-negative p38α (DNp38α) MAPK mice. Both β 1 -AR and β 2 -AR Tg mice had enhanced LV ejection fraction (LVEF) as young adults and developed similar cardiomyopathy at 11-15 months, characterized by reduced LVEF, myocyte hypertrophy, fibrosis, and apoptosis. We inhibited p38α MAPK by mating β 1 -AR Tg and β 2 -AR Tg mice with DNp38α MAPK mice, which rescued the depressed LVEF and reduced apoptosis and fibrosis in bigenic β 2 -AR × DNp38α MAPK mice, but not bigenic β 1 -AR × DNp38α MAPK mice, and failed to reduce myocyte hypertrophy in either group. G sα was increased in both β 1 -AR Tg and β 2 -AR Tg mice and was still present in bigenic β 1 -AR × DNp38α MAPK mice, but not bigenic β 2 -AR × DNp38α MAPK mice. This suggests that p38α MAPK is one critical downstream signal for the development of cardiomyopathy following chronic β 2 -AR stimulation, but other kinases may be more important in ameliorating the adverse effects of chronic β 1 -AR stimulation.
R-spondin (RSpo) proteins amplify Wnt signaling and stimulate regeneration in a variety of tissues. to repair tissue in a tissue-specific manner, tissue-targeted RSPO mimetic molecules are desired. Here, we mutated RSPO (RSPO2 F105R/F109A) to eliminate LGR binding while preserving ZNRF3/RNF43 binding and targeted the mutated RSPO to a liver specific receptor, ASGR1. The resulting bi-specific molecule (αASGR1-RSPO2-RA) enhanced Wnt signaling effectively in vitro, and its activity was limited to ASGR1 expressing cells. Systemic administration of αASGR1-RSPO2-RA in mice specifically upregulated Wnt target genes and stimulated cell proliferation in liver but not intestine (which is more responsive to non-targeted RSPO2) in healthy mice, and improved liver function in diseased mice. These results not only suggest that a tissue-specific RSPO mimetic protein can stimulate regeneration in a cell-specific manner, but also provide a blueprint of how a tissue-specific molecule might be constructed for applications in a broader context. The Wnt ("Wingless-related integration site" or "Wingless and Int-1" or "Wingless-Int") signaling pathway plays a key role in the development, homeostasis and regeneration of many essential organs and tissues 1. Timely activation, modulation, or enhancement of Wnt signaling holds potential for the treatment of various degenerative diseases and pathologies in which tissue regeneration could confer a therapeutic benefit. R-spondins 1-4 (RSPO1-4) are a family of ligands that amplify Wnt signals through a receptor complex containing the zinc and ring finger 3 (ZNRF3) and ring finger protein 43 (RNF43) proteins and the coreceptor leucine-rich repeat-containing G-protein coupled receptors 4-6 (LGR4-6) 2-4. RSPOs contain two furin (Fu) repeats, Fu1 and Fu2, which in combination are sufficient to recapitulate Wnt signaling enhancing activity 5. Fu1 primarily interacts with ZNRF3/RNF43 and Fu2 interacts with LGR4-6 5-7. ZNRF3 and RNF43 are membranebound E3 ligases that specifically target Wnt receptors (FZD1-10 and LRP5 or LRP6) for degradation 8,9. Binding of RSPOs to ZNRF3/RNF43 and LGR4-6 causes clearance or sequestration of the ternary complex, which stabilizes Wnt receptors and amplifies Wnt signaling. In addition, R-spondins might work through mechanisms that are independent of LGRs 10,11. RSPOs may be beneficial in adult tissue repair 12,13 , particularly in situations where the expression of endogenous Wnt ligands is upregulated but signaling (presumably limited by receptor stability) is insufficient to overcome tissue damage. In liver, RSPO function is important for metabolic zonation and for hepatocyte proliferation and regeneration 12,14. Therefore, RSPO may provide therapeutic benefit for various acute and chronic liver injury and diseases. One major challenge to exploring RSPO for tissue repair and regeneration is limiting RSPO effects to specific tissue of interest such as liver, as LGR4-6 and ZNRF3/RNF43 are widely expressed in various tissues. The mucosa of the gastrointestinal tract h...
In the present study, we tested the hypotheses that 1) different species have different myocardial adrenergic receptor numbers and 2) selected "slow-channel" calcium antagonists compete with alpha-adrenergic antagonists for binding to varying degrees in different species. The data obtained in the present study demonstrate that there is a markedly decreased number of alpha 1-adrenergic and increased number of beta-adrenergic receptors in canine compared with rabbit and rat myocardium. The differences in adrenergic receptor numbers exist without major differences in alpha 1-adrenergic receptor affinity in the species studied. There was no significant difference in left ventricular or plasma catecholamine content between the rat and dog. Selected slow-channel calcium antagonists compete for alpha 1-adrenergic receptor binding in rabbit, rat, and canine myocardium. However, only in rabbit myocardium does verapamil antagonize alpha 1-adrenergic receptor binding at moderate concentrations, whereas verapamil in canine and rat myocardium and 1) 600 in all three species antagonize alpha 1-adrenergic receptor binding only at relatively high concentrations. Nifedipine, a dihydropyridine-type slow-channel calcium antagonist, had no effect on prazosin binding to rat, rabbit, and dog myocardial membranes.
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