The outcome of infarct healing in mice strongly depends on genetic background. On the basis of our results, we suggest that for studies on infarct rupture, the 129S6 mouse is the background of choice, whereas BalbC and Swiss mice are the preferred models to study infarct thinning post-MI.

Abstract-The hypertrophic response of the heart has been recognized recently as the net result of activation of prohypertrophic and antihypertrophic pathways. Here we report the involvement of the Wnt/Frizzled pathway in the onset of cardiac hypertrophy development. Stimulation of the Wnt/Frizzled pathway activates the disheveled (Dvl) protein. Disheveled subsequently can inhibit glycogen synthase kinase-3␤, a protein with potent antihypertrophic actions through diverse molecular mechanisms. In the Wnt/Frizzled pathway, inhibition of glycogen synthase kinase-3␤ leads to an increased amount of ␤-catenin, which can act as a transcription factor for several hypertrophy-associated target genes. In this study we subjected mice lacking the Dvl-1 gene and their wild-type littermates to thoracic aortic constriction for 7, 14, and 35 days. In mice lacking the Dvl-1 gene, 7 days of pressure overload-induced increases in left ventricular posterior wall thickness and expression of atrial natriuretic factor and brain natriuretic protein were attenuated compared with their wild-type littermates. ␤-Catenin protein amount was reduced in the group lacking the Dvl-1 gene, and an increased glycogen synthase kinase-3␤ activity was observed. Moreover, the increase in the amount of Ser 473 -phosphorylated Akt, a stimulator of cardiac hypertrophy, was lower in the group lacking the Dvl-1 gene.In conclusion, we have demonstrated that interruption of Wnt signaling in the mice lacking the Dvl-1 gene attenuates the onset of pressure overload-induced cardiac hypertrophy through mechanisms involving glycogen synthase kinase-3␤ and Akt. Therefore, the Wnt/Frizzled pathway may provide novel therapeutic targets for antihypertrophic therapy. Key Words: hypertrophy Ⅲ Wnt Ⅲ cell signaling Ⅲ glycogen synthase kinase-3␤ Ⅲ Akt C ardiac hypertrophy is an adaptive response of the heart to an increased workload, caused by a variety of pathological stimuli, including hypertension, myocardial infarction, and valvular disease. Because cardiomyocytes are terminally differentiated, these cells can only respond by hypertrophic growth. 1 This growth is initially beneficial but a sustained hypertrophic response often leads to heart failure. 2 In this hypertrophic response, extracellular stimulation is translated into a cellular response, leading to changes in the contractile apparatus and to an activation of many signaling pathways. 3 Several of these signaling pathways transduce prohypertrophic signals, but it has been shown that a number of endogenous molecules can regulate the hypertrophic response negatively. 4 One of the most powerful negative regulators that can antagonize the hypertrophic response is glycogen synthase kinase-3␤ (GSK-3␤), a ubiquitous serine/threonine protein kinase. 4,5 GSK-3␤ is a downstream regulatory switch of multiple signaling pathways that regulates a wide range of cellular functions. 6 Dysregulation of GSK-3␤ plays a role in many human diseases, including diabetes, Alzheimer's disease, bipolar disorder, cancer, 7 and heart failur...

Phagocytosis of IgG-opsonized participate material in hematopoietic cells is mediated by Fey receptors (FcyRs).Interaction of the receptors with Fc domains of IgG triggers transduction of phagocytic signal in which a key role is played by phosphorylation of tyrosine residues of the receptors. These residues are arranged into a specific motif (immunoreceptor tyrosine-based activation motif; ITAM) which is located either in the cytoplasmic part of FeyRIIA or in γchains associated with FeyRI and FcyRIIIA. The conserved tyrosine residues are phosphorylated by, and associate with, tyrosine kinases of Src and Syk families. Coordinated action of these components initiates numerous intracellular events leading finally to local rearrangement of the actin-based cytoskeleton and internalization of the particles.

Objective The diabetic heart is characterized by extensive lipid accumulation which often leads to cardiac contractile dysfunction. The underlying mechanism involves a pivotal role for vacuolar-type H + -ATPase (v-ATPase, functioning as endosomal/lysosomal proton pump). Specifically, lipid oversupply to the heart causes disassembly of v-ATPase and endosomal deacidification. Endosomes are storage compartments for lipid transporter CD36. However, upon endosomal deacidification, CD36 is expelled to translocate to the sarcolemma, thereby inducing myocardial lipid accumulation, insulin resistance, and contractile dysfunction. Hence, the v-ATPase assembly may be a suitable target for ameliorating diabetic cardiomyopathy. Another function of v-ATPase involves the binding of anabolic master-regulator mTORC1 to endosomes, a prerequisite for the activation of mTORC1 by amino acids (AAs). We examined whether the relationship between v-ATPase and mTORC1 also operates reciprocally; specifically, whether AA induces v-ATPase reassembly in a mTORC1-dependent manner to prevent excess lipids from entering and damaging the heart. Methods Lipid overexposed rodent/human cardiomyocytes and high-fat diet-fed rats were treated with a specific cocktail of AAs (lysine/leucine/arginine). Then, v-ATPase assembly status/activity, cell surface CD36 content, myocellular lipid uptake/accumulation, insulin sensitivity, and contractile function were measured. To elucidate underlying mechanisms, specific gene knockdown was employed, followed by subcellular fractionation, and coimmunoprecipitation. Results In lipid-overexposed cardiomyocytes, lysine/leucine/arginine reinternalized CD36 to the endosomes, prevented/reversed lipid accumulation, preserved/restored insulin sensitivity, and contractile function. These beneficial AA actions required the mTORC1–v-ATPase axis, adaptor protein Ragulator, and endosomal/lysosomal AA transporter SLC38A9, indicating an endosome-centric inside-out AA sensing mechanism. In high-fat diet-fed rats, lysine/leucine/arginine had similar beneficial actions at the myocellular level as in vitro in lipid-overexposed cardiomyocytes and partially reversed cardiac hypertrophy. Conclusion Specific AAs acting through v-ATPase reassembly reduce cardiac lipid uptake raising the possibility for treatment in situations of lipid overload and associated insulin resistance.