In the infarcted myocardium, activation of the inflammatory cascade clears the wound from dead cells, while stimulating matrix degradation and chamber dilation, thus contributing to the development of heart failure. IL-1 is critically involved in the post-infarction inflammatory reaction and mediates adverse dilative remodeling. We hypothesized that IL-1 may regulate post-infarction repair and remodeling through cell-specific actions on leukocytes and fibroblasts. Flow cytometry demonstrated that in mouse infarcts, early recruitment of pro-inflammatory Ly6Chi cells expressing IL-1R1, the signaling receptor for IL-1, was followed by infiltration with cells expressing the decoy receptor, IL-1R2. Increased expression of IL-1R2 may serve to terminate IL-1-driven inflammation following infarction. Loss of IL-1 signaling in IL-1R1 null mice globally attenuated leukocyte recruitment, reducing the number of infiltrating Ly6Chi and Ly6Clo cells. Non-myeloid CD11b-negative cells harvested during the inflammatory phase of cardiac repair exhibited marked upregulation of chemokines and cytokines; their inflammatory activation was IL-1R1-dependent. Moreover, IL-1β attenuated TGF-β-induced contractile activity of fibroblasts populating collagen pads, attenuated α-smooth muscle actin expression and stimulated matrix metalloproteinase synthesis in an IL-1R1-dependent manner. The effects of IL-1 on TGF-β responses in cardiac fibroblasts were not due to direct effects on Smad activation, but were associated with endoglin suppression and accentuated expression of BAMBI, a negative regulator of TGF-β signaling. IL-1 may orchestrate fibroblast responses in the infarct; early stimulation of fibroblast IL-1R1 signaling during the inflammatory phase may prevent premature activation of a matrix-synthetic contractile phenotype until the wound is cleared, and the infarct microenvironment can support mesenchymal cell growth.

Kong P, Christia P, Saxena A, Su Y, Frangogiannis NG. Lack of specificity of fibroblast-specific protein 1 in cardiac remodeling and fibrosis. Am J Physiol Heart Circ Physiol 305: H1363-H1372, 2013. First published August 30, 2013; doi:10.1152/ajpheart.00395.2013Understanding the role of fibroblasts in pathologic conditions is hampered by the absence of specific markers. Fibroblast-specific protein (FSP)1 has been suggested as a fibroblast-specific marker in normal and fibrotic tissues; FSP1 reporter mice and FSP1-Cre-driven gene deletion are considered reliable strategies to investigate fibroblast biology. Because fibroblasts are abundant in normal and injured mammalian hearts, we studied the identity of FSP1 ϩ cells in the infarcted and remodeling myocardium using mice with green fluorescent protein (GFP) expression driven by the FSP1 promoter. Neonatal and adult mouse hearts had low numbers of FSP1 ϩ cells. Myocardial infarction induced marked infiltration with FSP1-expressing cells that peaked after 72 h of reperfusion. Using flow cytometry, we identified 50% of FSP1 ϩ cells as hematopoietic cells; many endothelial cells were also FSP1ϩ . Increased infiltration with FSP1 ϩ cells was also noted in the pressure-overloaded myocardium. Although some FSP1 ϩ cells had fibroblast morphology, Ͼ30% were identified as hematopoietic cells, endothelial cells, or vascular smooth muscle cells. In contrast, periostin did not stain leukocytes or vascular cells but labeled spindle-shaped interstitial cells and, as a typical matricellular protein, was deposited in the matrix. CD11b ϩ myeloid cells sorted from the infarcted heart had higher FSP1 expression than corresponding CD11b-negative cells, highlighting the predominant expression by hematopoietic cells. FSP1 is not a specific marker for fibroblasts in cardiac remodeling and fibrosis. cardiac fibrosis; myocardial infarction; fibroblast; cardiac remodeling; periostin FIBROBLASTS ARE THE MOST ABUNDANT noncardiomyocytes in the adult mammalian myocardium and play an important role in cardiac homeostasis and disease (39). In the normal heart, fibroblasts not only secrete extracellular matrix proteins and provide structural support by maintaining the interstitial matrix network but may also interact with cardiomyocytes and vascular cells transducing signals essential for preservation of cardiac function (21, 42). Following myocardial injury, cardiac fibroblasts undergo dynamic changes and actively participate in reparative, fibrotic, and hypertrophic responses (9) by secreting structural and matricellular matrix proteins and by releasing cytokines and growth factors, thus modulating phenotype and function of cardiomyocytes and noncardiomyocytes (23, 41). Because of their abundance in normal and injured hearts, their phenotypic plasticity, and their broad range of secreted mediators, fibroblasts have attracted significant interest as potentially critical cellular effectors of cardiac remodeling. However, understanding of their role in vivo has been hampered by the lack of a reli...

SUMMARY Hypothalamic neurons expressing Agouti-related peptide (AgRP) are critical for initiating food intake. But druggable biochemical pathways that control this response remain elusive. Thus, genetic ablation of anorexigenic signaling by insulin or leptin in AgRP neurons fails to affect food intake. FoxO1 is a shared mediator of both pathways, and its inhibition is required for their anorexigenic effects. We postulated that FoxO1 effectors include pathways regulating food intake. Accordingly, FoxO1 ablation in AgRP neurons of mice results in reduced food intake, leanness, improved glucose homeostasis, and increased sensitivity to insulin and leptin. Expression profiling of flow-sorted FoxO1-deficient AgRP neurons identifies G protein-coupled receptor Gpr17 as a FoxO1 target whose expression is regulated by nutritional status. Intracerebroventricular injection of Gpr17 agonists induces food intake, while Gpr17 antagonist cangrelor curtails it. These effects are absent in Agrp-Foxo1 knockouts, suggesting that pharmacological modulation of this pathway has therapeutic potential to treat obesity.

In healing myocardial infarction, myofibroblast- and cardiomyocyte-specific activation of Smad3 has contrasting functional outcomes that may involve activation of an integrin/reactive oxygen axis.

Increased endogenous glucose production (EGP) is a hallmark of type 2 diabetes mellitus. While there is evidence for central regulation of EGP by activation of hypothalamic ATP-sensitive potassium (K ATP ) channels in rodents, whether these central pathways contribute to regulation of EGP in humans remains to be determined. Here we present evidence for central nervous system regulation of EGP in humans that is consistent with complementary rodent studies. Oral administration of the K ATP channel activator diazoxide under fixed hormonal conditions substantially decreased EGP in nondiabetic humans and Sprague Dawley rats. In rats, comparable doses of oral diazoxide attained appreciable concentrations in the cerebrospinal fluid, and the effects of oral diazoxide were abolished by i.c.v. administration of the K ATP channel blocker glibenclamide. These results suggest that activation of hypothalamic K ATP channels may be an important regulator of EGP in humans and that this pathway could be a target for treatment of hyperglycemia in type 2 diabetes mellitus.