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Articles by C Steenbergen
Total Records ( 3 ) for C Steenbergen
  J Lin , C Steenbergen , E Murphy and J. Sun
 

Background— It has been shown that the activation of estrogen receptor-β (ER-β) plays an important cardioprotective role against ischemia/reperfusion injury. However, the mechanism for this protection is not clear. We hypothesize that estrogen protects by ER-β activation, which leads to S-nitrosylation (SNO) of key cardioprotective proteins.

Methods and Results— We treated ovariectomized C57BL/6J mice with the ER-β selective agonist 2,2-bis(4-hydroxyphenyl)-proprionitrile (DPN), 17β-estradiol (E2), or vehicle using Alzet minipumps for 2 weeks. Isolated hearts were Langendorff perfused and subjected to ischemia and reperfusion. Compared with vehicle-treated hearts, DPN- and E2-treated hearts had significantly better postischemic functional recovery and decreased infarct size. To test the specificity of DPN, we treated ER-β–knockout mice with DPN. However, no cardioprotective effect of DPN was found in ER-β–knockout mice, indicating that the DPN-induced cardioprotection occurs through the activation of ER-β. Using DyLight-maleimide fluors and a modified biotin switch method, we used a 2-dimensional DyLight fluorescence difference gel electrophoresis proteomic method to quantify differences in SNO of proteins. DPN- and E2-treated hearts showed an increase in SNO of a number of proteins. Interestingly, many of these proteins also had been shown to have increased SNO in preconditioned hearts. In addition, the DPN-induced cardioprotection and increased SNO were abolished by treatment with a nitric oxide synthase inhibitor.

Conclusion— The activation of ER-β by DPN treatment leads to increased protein SNO and cardioprotection against ischemia/reperfusion injury, suggesting that long-term estrogen exposure protects hearts largely via activation of ER-β and nitric oxide/SNO signaling.

  P. V Johnston , T Sasano , K Mills , R Evers , S. T Lee , R. R Smith , A. C Lardo , S Lai , C Steenbergen , G Gerstenblith , R Lange and E. Marban
 

Background— Cardiosphere-derived cells (CDCs) isolated from human endomyocardial biopsies reduce infarct size and improve cardiac function in mice. Safety and efficacy testing in large animals is necessary for clinical translation.

Methods and Results— Mesenchymal stem cells, which resemble CDCs in size and thrombogenicity, have been associated with infarction after intracoronary infusion. To maximize CDC engraftment while avoiding infarction, we optimized the infusion protocol in 19 healthy pigs. A modified cocktail of CDCs in calcium-free PBS, 100 U/mL of heparin, and 250 µg/mL of nitroglycerin eliminated infusion-related infarction. Subsequent infusion experiments in 17 pigs with postinfarct left ventricular dysfunction showed CDC doses ≥107 but <2.5x107 result in new myocardial tissue formation without infarction. In a pivotal randomized study, 7 infarcted pigs received 300 000 CDCs/kg (107 total) and 7 received placebo (vehicle alone). Cardiac magnetic resonance imaging 8 weeks later showed CDC treatment decreased relative infarct size (19.2% to 14.2% of left ventricle infarcted, P=0.01), whereas placebo did not (17.7% to 15.3%, P=0.22). End-diastolic volume increased in placebo, but not in CDC-treated animals. Hemodynamically, the rate of pressure change (dP/dt) maximum and dP/dt minimum were significantly better with CDC infusion. There was no difference between groups in the ability to induce ventricular tachycardia, nor was there any tumor or ectopic tissue formation.

Conclusions— Intracoronary delivery of CDCs in a preclinical model of postinfarct left ventricular dysfunction results in formation of new cardiac tissue, reduces relative infarct size, attenuates adverse remodeling, and improves hemodynamics. The evidence of efficacy without obvious safety concerns at 8 weeks of follow-up motivates human studies in patients after myocardial infarction and in chronic ischemic cardiomyopathy.

 
 
 
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