Cardioprotective proteins upregulated in the liver in response to experimental myocardial ischemia

Abstract

Myocardial ischemia (MI) activates innate cardioprotective mechanisms, enhancing cardiomyocyte tolerance to ischemia. Here, we report a MI-activated liver-dependent mechanism for myocardial protection. In response to MI in the mouse, hepatocytes exhibited 6- to 19-fold upregulation of genes encoding secretory proteins, including α-1-acid glycoprotein (AGP)2, bone morphogenetic protein-binding endothelial regulator (BMPER), chemokine (C-X-C motif) ligand 13, fibroblast growth factor (FGF)21, neuregulin (NRG)4, proteoglycan 4, and trefoil factor (TFF)3. Five of these proteins, including AGP2, BMPER, FGF21, NRG4, and TFF3, were identified as cardioprotective proteins since administration of each protein significantly reduced the fraction of myocardial infarcts (37 ± 9%, 34 ± 7%, 32 ± 8%, 39 ± 6%, and 31 ± 7%, respectively, vs. 48 ± 7% for PBS at 24 h post-MI). The serum level of the five proteins elevated significantly in association with protein upregulation in hepatocytes post-MI. Suppression of a cardioprotective protein by small interfering (si)RNA-mediated gene silencing resulted in a significant increase in the fraction of myocardial infarcts, and suppression of all five cardioprotective proteins with siRNAs further intensified myocardial infarction. While administration of a single cardioprotective protein mitigated myocardial infarction, administration of all five proteins furthered the beneficial effect, reducing myocardial infarct fractions from PBS control values from 46 ± 6% (5 days), 41 ± 5% (10 days), and 34 ± 4% (30 days) to 35 ± 5%, 28 ± 5%, and 24 ± 4%, respectively. These observations suggest that the liver contributes to cardioprotection in MI by upregulating and releasing protective secretory proteins. These proteins may be used for the development of cardioprotective agents.

Molecular evidence of stress-induced acute heart injury in a mouse model simulating posttraumatic stress disorder

“…Elevating the adenosine level in the heart causes vasodilation and an increase in heart rate (33). Adenosine has been implicated in the initial injury process, because it is a well-known signaling molecule for stress and tissue injury (34)(35)(36). From this study, we observed a gradual increase in the adenosine deaminase transcript level (peaking in the T3R1 group).…”

Unique Features of Cortical Bone Stem Cells Associated With Repair of the Injured Heart

“…Several growth, paracrine, and autocrine factors are released by stem cells if/when they arrive at the site of injury. 20 sCBSCs, CDCs, and MSCs all showed chemotaxis for most of the paracrine factors, including bFGF, HGF, VEGF, IGF-1, stromal-derived growth factor 1, platelet-derived growth factor, and TGF-β. CBSCs showed increased migration toward TGF-β compared with CDCs and MSCs (CBSCs versus CDCs and MSCs; P<0.001; Figure 2G).…”

“…2 pCBSCs, CDCs, and MSCs were plated in a 6-well dish (30 000 cells/well) and incubated in their respective medium without serum overnight and then treated with 10,20,30,40, and 50 μmol/L H 2 O 2 overnight. Cell death was confirmed by visualizing the cells under a light microscope before collection.…”

Fibroblast Activation Protein (FAP) Accelerates Collagen Degradation and Clearance from Lungs in Mice

“…This may at first seem counterintuitive as proteins up-regulated in disease tend to serve a pathologic role. However, the scientific literature catalogues a growing number of proteins up-regulated in disease that work to counter the disease process, reestablish homeostasis, and return the body to its original state of health (61)(62)(63), and we have found that FAP behaves in such a fashion in pulmonary fibrosis. This study is the first to demonstrate that the absence of FAP worsens the development of pulmonary fibrosis after lung injury, establishing a protective role for FAP in the lung.…”