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Heme oxygenase-1 induction enhances cell survival and restores contractility to unvascularized three-dimensional adult cardiomyocyte grafts implanted in vivo.

ABSTRACT: Autologous adult cardiomyocytes are not utilized for heart repair strategies because of their rapid apoptosis after implantation. We examined whether induction of heme oxygenase-1 (HO-1), a mediator of preconditioning, could enhance early postimplant myocyte survival. Three-dimensional 5×5 mm patches of full-thickness adult murine atrial wall, including cardiomyocytes, capillary networks, and extracellular matrix, were cultured with or without HO-1 inducer cobalt protoporphyrin (CoPP), or the HO-1 inhibitor, tin protoporphyrin (SnPP), or both. Patches were then implanted subcutaneously. Freshly procured atrial wall patches implanted without preculturing served as additional controls. By 14 days postimplant, graft cardiomyocyte content was significantly greater in CoPP-treated patches than in either control group (p<0.02). Adult cardiomyocytes did not contract in culture or immediately after implantation. However, by 14 days postimplant, spontaneous contraction had recovered in 47% of CoPP-treated patches, but in only 6% of precultured patches without CoPP, 0% of SnPP-treated patches, and 0% of uncultured patches (p<0.03). CoPP-treated adult cardiomyocyte patches were also observed to remodel spontaneously into endothelial-lined chambers that pumped nonclotting blood. These findings demonstrate that adult cardiomyocytes have more plasticity and capacity for functional recovery than previously recognized and could have application as an autologous cardiomyocyte source for tissue engineering.

SUBMITTER: Kawamoto S

PROVIDER: S-EPMC3098958 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Estrogen-induced cholestasis is characterized by impaired hepatic uptake and biliary bile acids secretion because of changes in hepatocyte transporter expression. The induction of heme oxygenase-1 (HMOX1), the inducible isozyme in heme catabolism, is mediated via the Bach1/Nrf2 pathway, and protects livers from toxic, oxidative and inflammatory insults. However, its role in cholestasis remains unknown. Here, we investigated the effects of HMOX1 induction by heme on ethinylestradiol-induced cholestasis and possible underlying mechanisms. Wistar rats were given ethinylestradiol (5 mg/kg s.c.) for 5 days. HMOX1 was induced by heme (15 ?mol/kg i.p.) 24 hrs prior to ethinylestradiol. Serum cholestatic markers, hepatocyte and renal membrane transporter expression, and biliary and urinary bile acids excretion were quantified. Ethinylestradiol significantly increased cholestatic markers (P ? 0.01), decreased biliary bile acid excretion (39%, P = 0.01), down-regulated hepatocyte transporters (Ntcp/Oatp1b2/Oatp1a4/Mrp2, P ? 0.05), and up-regulated Mrp3 (348%, P ? 0.05). Heme pre-treatment normalized cholestatic markers, increased biliary bile acid excretion (167%, P ? 0.05) and up-regulated hepatocyte transporter expression. Moreover, heme induced Mrp3 expression in control (319%, P ? 0.05) and ethinylestradiol-treated rats (512%, P ? 0.05). In primary rat hepatocytes, Nrf2 silencing completely abolished heme-induced Mrp3 expression. Additionally, heme significantly increased urinary bile acid clearance via up-regulation (Mrp2/Mrp4) or down-regulation (Mrp3) of renal transporters (P ? 0.05). We conclude that HMOX1 induction by heme increases hepatocyte transporter expression, subsequently stimulating bile flow in cholestasis. Also, heme stimulates hepatic Mrp3 expression via a Nrf2-dependent mechanism. Bile acids transported by Mrp3 to the plasma are highly cleared into the urine, resulting in normal plasma bile acid levels. Thus, HMOX1 induction may be a potential therapeutic strategy for the treatment of ethinylestradiol-induced cholestasis.

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Heme oxygenase-1 induction enhances cell survival and restores contractility to unvascularized three-dimensional adult cardiomyocyte grafts implanted in vivo.

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