A 61-year-old man with a history of hypertension, coronary artery disease (CAD) with prior stent placement, and chronic obstructive pulmonary disease (COPD) presented with a 4-month history of recurrent pleural effusions and progressive diffuse edema.
Divalent metal‐ion transporter‐1 (DMT1)—the product of the SLC11A2 gene—is a widely expressed iron transporter serving intestinal iron absorption and erythroid iron utilization. We tested the hypothesis that DMT1 is essential for intestinal absorption of iron by examining hematological variables, iron stores, and expression of iron‐related genes (by using real‐time qPCR) in a mouse model lacking intestinal DMT1 (i.e. DMT1int/int), males at age ≈ 120 days. Generation of the DMT1int/int model, by crossing floxed DMT1 and villin‐Cre transgenic lines, was described previously [Gunshin et al (2005) J. Clin. Investig.115, 1258–1266]. The DMT1int/int mouse exhibited a severe microcytic– hypochromic anemia—characterized by profound decreases in hematocrit, hemoglobin concentration (DMT1int/int, 2.3 ± SD 1.5 g/dL cf. wildtype, 14.6 ± 0.7 g/dL; n = 7–9), mean corpuscular volume, and serum iron—accompanied by cardiac hypertrophy, splenomegaly, and severely depleted nonheme iron stores (liver, spleen). mRNA expression of the brush‐border ferrireductase Cybrd1 was increased (30 ± 3)‐fold in enterocytes of DMT1int/int mice cf. wildtype mice (mean ± propagated SE, n = 3) and mRNA expression of the basolateral iron‐exporter ferroportin was increased (2.7 ± 1.0)‐fold. Liver Hamp1 (hepcidin) mRNA expression was depressed by 98% ± 42% in the DMT1int/int mouse cf. wildtype. Intraperitoneal iron injection corrected the hematological variables, iron stores, and mRNA expression levels in the DMT1int/int mouse. Our data reveal that tissue‐specific ablation of intestinal DMT1 produces an iron‐deficiency anemia, and confirm that DMT1 is critical for iron homeostasis in the mouse. PHS Grant DK080047
The heart protects itself from injury through protective intrinsic mechanisms. Understanding the mechanisms that elicit this cardioprotective effect is vital to the prevention of myocardial infarction. It has been established in the Jones Lab that an acute high fat diet elicits a cardioprotective effect in a murine model. The adipose‐derived circulating adipokine adiponectin may play a crucial role in the activation of cardioprotective gene programs in this high fat model as it has been previously shown to be cardioprotective. This study will address the hypothesis that high fat diet mediates cardioprotection through circulating adiponectin acting through receptors in the heart that activate autophagic and anti‐apoptotic programs necessary for preconditioning. To address this hypothesis, an in vitro model was established by simulating I/R in HL‐1 cells, and a surgical model that utilizes 30 minute occlusion of the LAD to create infarct. Beclin‐1 (a marker of autophagy) expression was assessed in mice after a 24hr high fat diet through western blot analysis. From these results, we are able to establish that an acute high fat diet elicits a cardioprotective effect in a murine model. Furthermore, the cardioprotective effect of the high fat diet is lost in adiponectin knockout mice, meaning that adiponectin is a key player in high fat mediated cardioprotection. The upregulation of Beclin‐1 after a high fat diet suggests that adiponectin and the high fat diet is priming the cells for an autophagic state. Beclin‐1 is a downstream target of NF‐κB, a key player in cardioprotective mechanism, and this suggests that adiponectin is interacting with NF‐κB and eliciting a cardioprotective effect. Grant Funding Source: Provost Pilot Grant‐University of Cincinnati(COM)
Prolonged high fat diet (HFD) consumption leads to diverse pathologies such as obesity, type II diabetes, atherosclerosis, and myocardial infarction. Paradoxically, studies have shown that short term HFD is cardioprotective against myocardial ischemia and reperfusion (I/R). This response is NF‐κB dependent, a hallmark of preconditioning pathways. This study will address the hypothesis that the adipose‐derived circulating cytokine, adiponectin promotes the activation of NF‐κB in an acute HFD by acting on cardiac receptors and stimulating cardioprotective gene programs. To investigate this in an intact in vivo AdipoQ KO model, infarct size formed in 24h HFD and ctrl chow fed mice were compared. In vitro studies employed HL‐1 cells treated with adipocyte conditioned or ctrl medium to assess a direct response of adiponectin on cardiomyocytes after undergoing a simulated I/R (sim I/R) event in a hypoxic chamber. Cell death was measured by lactate dehydrogenase assay and NF‐κB activation was indirectly measured through the activation downstream NF‐κB ‐dependent genes (VEGF, HIF1a) by qRT‐PCR. Results showed no significant difference in infarct size between the HFD and ctrl chow AdKO mice suggesting the loss of HFD cardioprotection due to loss of adiponectin. Furthermore, treatment in conditioned medium demonstrated significantly reduced cell death and upregulation of NF‐κB‐dependent gene programs after sim I/R in comparison to untreated cells. Our data supports adiponectin as a crucial molecular activator in acute HFD cardioprotection.
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