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A Novel Hydrogen Sulfide Donor, JK1 Protects the Heart Against Cardiac Hypertrophy and Heart Failure
Author(s) -
Li Zhen,
Organ Chelsea L.,
Kang Jianming,
Xian Ming,
Lefer David J.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb543
Subject(s) - medicine , heart failure , cardiac function curve , cardiology , myocardial infarction , ischemia , oxidative stress , reperfusion injury , in vivo , pharmacology , microbiology and biotechnology , biology
Background and Hypothesis Hydrogen sulfide (H 2 S) protects against acute myocardial ischemia/reperfusion injury and heart failure by ameliorating oxidative stress, improving mitochondrial function, and attenuating apoptosis. One major limitation in the development of H 2 S‐based therapy is a lack of evidence supporting its cardioprotective effects in a clinically relevant scenario that mimics heart failure in humans. A second limitation related to the development of H 2 S therapeutics for heart failure is the very poor pharmacokinetic profile of most H 2 S‐donating agents. In the present study we tested the efficacy of a novel H 2 S donor, JK1, with controlled H 2 S release and increased half‐life compared to traditional H 2 S‐releasing agents. We evaluated JK1 in a clinically relevant murine model of transverse aortic constriction (TAC) induced heart failure (HF). We hypothesized that delayed administration of JK1 would protect the myocardium against TAC‐induced heart failure. Methods Male C57/BL6J at 10 weeks (wks) of age were subjected to TAC (27G needle) for 12 wks. Optimal dosing of JK1 was determined from preliminary studies of in vivo myocardial ischemia and reperfusion in which 100 μg/kg JK1 treatment reduced myocardial infarct size from 48.19% to 17.44%. JK1 (100 μg/kg/d, n=16) or control compound (100 μg/kg/d, n=15) were administered (i.p.) starting at 3 wks post TAC. Echocardiography was performed at baseline and following TAC to assess cardiac function. Results Delayed treatment of JK1 significantly preserved left ventricular (LV) ejection fraction (LVEF 49.7% vs. 36.2%, p < 0.001), reduced left ventricular dilation (LVEDD/LVESD in mm): 3.77/2.81 vs. 4.34/3.50, p < 0.001), and attenuated eccentric hypertrophy (IVSD in mm: 0.84 vs. 1.00, p < 0.01. LVPWd in mm: 0.78 vs. 0.89, p < 0.05) at 12 wks post TAC as compared to Control. Complete data for LVEF and % LV fractional shortening (FS) are shown below. Conclusion These results demonstrate that delayed administration of JK1 significantly preserves LV function and attenuates adverse remodeling in HF. Studies are currently underway to define the molecular mechanisms involved in JK1 mediated cardioprotection. Support or Funding InformationAcknowledgement: This work was supported by the National Institutes of Health (R01HL116571).