Adrienne L King

Emory University, Atlanta, GA, United States

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Publications (9)53.88 Total impact

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    ABSTRACT: Previous studies have demonstrated that hydrogen sulfide (H2S) protects against multiple cardiovascular disease states in a similar manner as nitric oxide (NO). H2S therapy also has been shown to augment NO bioavailability and signaling. The purpose of this study was to investigate the impact of H2S deficiency on endothelial NO synthase (eNOS) function, NO production, and ischemia/reperfusion (I/R) injury. We found that mice lacking the H2S-producing enzyme cystathionine γ-lyase (CSE) exhibit elevated oxidative stress, dysfunctional eNOS, diminished NO levels, and exacerbated myocardial and hepatic I/R injury. In CSE KO mice, acute H2S therapy restored eNOS function and NO bioavailability and attenuated I/R injury. In addition, we found that H2S therapy fails to protect against I/R in eNOS phosphomutant mice (S1179A). Our results suggest that H2S-mediated cytoprotective signaling in the setting of I/R injury is dependent in large part on eNOS activation and NO generation.
    Proceedings of the National Academy of Sciences 02/2014; · 9.81 Impact Factor
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    ABSTRACT: BACKGROUND: Cystathionine gamma-lyase (CSE) produces H(2)S via enzymatic conversion of L-cysteine and plays a critical role in cardiovascular homeostasis. We investigated the effects of genetic modulation of CSE and exogenous H(2)S therapy in the setting of pressure overload-induced heart failure. METHODS AND RESULTS: Transverse aortic constriction (TAC) was performed in wild-type (WT), CSE knockout (KO), and cardiac specific CSE transgenic (CS-CSE Tg) mice. In addition, C57BL/6J or CSE KO mice received a novel H(2)S donor (SG-1002). Mice were followed for 12 weeks using echocardiography. We observed a >60% reduction in myocardial and circulating H(2)S levels following TAC. CSE KO mice exhibited cardiac dilatation and dysfunction significantly greater than WT mice following TAC and CS-CSE Tg mice maintained cardiac structure and function following TAC. H(2)S therapy with SG-1002 resulted in cardioprotection during TAC via upregulation of the VEGF-Akt-eNOS-nitric oxide-cGMP pathway with preserved mitochondrial function, attenuated oxidative stress, and increased myocardial vascular density. CONCLUSIONS: Our results demonstrate that H(2)S levels are decreased in mice in the setting of heart failure. Moreover, CSE plays a critical role in the preservation of cardiac function in heart failure and oral H(2)S therapy prevents the transition from compensated to decompensated heart failure in part via upregulation of endothelial nitric oxide synthase (eNOS) and increased NO bioavailability.
    Circulation 02/2013; · 15.20 Impact Factor
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    ABSTRACT: β(2)-adrenoreceptor activation has been shown to protect cardiac myocytes from cell death. We hypothesized that acute β(2)-adrenoreceptor stimulation, using arformoterol (ARF), would attenuate myocardial ischemia/reperfusion (R) injury via NO synthase activation and cause a subsequent increase in NO bioavailability. Male C57BL/6J and endothelial NO synthase (eNOS) knockout mice were subjected to 45 minutes of myocardial ischemia and 24 hours of R. ARF or vehicle was administered 5 minutes before R. Serum troponin-I was measured, and infarct size per area-at-risk was evaluated at 24 hours of R. Echocardiography was performed at baseline and 2 weeks after R. Myocardial cAMP, protein kinase A, eNOS/Akt phosphorylation status, and NO metabolite levels were assayed. ARF (1 µg/kg) reduced infarct size per area-at-risk by 53.1% (P<0.001 versus vehicle) and significantly reduced troponin-I levels (P<0.001 versus vehicle). Ejection fraction was significantly preserved in ARF-treated hearts compared with vehicle hearts at 2 weeks of R. Serum cAMP and nuclear protein kinase A C-α increased 5 and 15 minutes after ARF injection, respectively (P<0.01). ARF increased Akt phosphorylation at Thr(308) (P<0.001) and Ser(473) (P<0.01), and eNOS phosphorylation at Ser(1177) (P<0.01). ARF treatment increased heart nitrosothiol levels (P<0.001) at 15 min after injection. ARF failed to reduce infarct size in eNOS(-/-) mice. Our results indicate that β(2)-adrenoreceptor stimulation activates cAMP, protein kinase A, Akt, and eNOS and augments NO bioavailability. Activation of this prosurvival signaling pathway attenuates myocardial cell death and preserves cardiac function after ischemia/reperfusion.
    Arteriosclerosis Thrombosis and Vascular Biology 05/2012; 32(8):1865-74. · 6.34 Impact Factor
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    ABSTRACT: Diallyl trisulfide (DATS), a polysulfide constituent found in garlic oil, is capable of the release of hydrogen sulfide (H(2)S). H(2)S is a known cardioprotective agent that protects the heart via antioxidant, antiapoptotic, anti-inflammatory, and mitochondrial actions. Here, we investigated DATS as a stable donor of H(2)S during myocardial ischemia-reperfusion (MI/R) injury in vivo. We investigated endogenous H(2)S levels, infarct size, postischemic left ventricular function, mitochondrial respiration and coupling, endothelial nitric oxide (NO) synthase (eNOS) activation, and nuclear E2-related factor (Nrf2) translocation after DATS treatment. Mice were anesthetized and subjected to a surgical model of MI/R injury with and without DATS treatment (200 μg/kg). Both circulating and myocardial H(2)S levels were determined using chemiluminescent gas chromatography. Infarct size was measured after 45 min of ischemia and 24 h of reperfusion. Troponin I release was measured at 2, 4, and 24 h after reperfusion. Cardiac function was measured at baseline and 72 h after reperfusion by echocardiography. Cardiac mitochondria were isolated after MI/R, and mitochondrial respiration was investigated. NO metabolites, eNOS phosphorylation, and Nrf2 translocation were determined 30 min and 2 h after DATS administration. Myocardial H(2)S levels markedly decreased after I/R injury but were rescued by DATS treatment (P < 0.05). DATS administration significantly reduced infarct size per area at risk and per left ventricular area compared with control (P < 0.001) as well as circulating troponin I levels at 4 and 24 h (P < 0.05). Myocardial contractile function was significantly better in DATS-treated hearts compared with vehicle treatment (P < 0.05) 72 h after reperfusion. DATS reduced mitochondrial respiration in a concentration-dependent manner and significantly improved mitochondrial coupling after reperfusion (P < 0.01). DATS activated eNOS (P < 0.05) and increased NO metabolites (P < 0.05). DATS did not appear to significantly induce the Nrf2 pathway. Taken together, these data suggest that DATS is a donor of H(2)S that can be used as a cardioprotective agent to treat MI/R injury.
    AJP Heart and Circulatory Physiology 03/2012; 302(11):H2410-8. · 4.01 Impact Factor
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    ABSTRACT: sulfide and increasing nitric oxide bioavailability myocardium by preservation of endogenous hydrogen The polysulfide diallyl trisulfide protects the ischemic intact animal to the cellular, subcellular, and molecular levels. It is published 12 times a year (monthly) by the American lymphatics, including experimental and theoretical studies of cardiovascular function at all levels of organization ranging from the publishes original investigations on the physiology of the heart, blood vessels, and AJP -Heart
    AJP Heart and Circulatory Physiology 01/2012; · 4.01 Impact Factor
  • Angewandte Chemie International Edition 08/2011; 50(41):9672-5. · 11.34 Impact Factor
  • Adrienne L King, David J Lefer
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    ABSTRACT: Hydrogen sulfide (H(2)S) has been known as a highly toxic gas for several centuries. There have been considerable advances made in the H(2)S field regarding its physiological role; however, there is much more work that needs to be done. The biosynthesis of H(2)S has been attributed to three endogenous enzymes: cystathionine β-synthase (CBS), cystathionine γ-lyase (CGL or CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST). These enzymes require further investigation to more fully elucidate the cellular expression profile, regulation and precise role of these critical enzymes in the production of H(2)S. In recent years, H(2)S has been demonstrated to have cytoprotective effects in multiple organ systems. In particular, it has been demonstrated that the administration of H(2)S either prior to ischaemia or at reperfusion significantly ameliorates myocardial and hepatic ischaemia-reperfusion injury. Therefore, this review focuses on the cardioprotective and hepatoprotective role of H(2)S. In addition, the review provides a summary of several known molecular targets of H(2)S protection.
    Experimental physiology 06/2011; 96(9):840-6. · 3.17 Impact Factor
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    ABSTRACT: Background Hydrogen sulfide (H2S) is enzymatically formed in the heart and vasculature from cysteine via cystathionine γ-lyase (CSE). H2S is a critically important physiological signaling molecule that acts in concert with nitric oxide (NO) to attenuate oxidative stress, inflammation, and apoptosis during pathological conditions. The purpose of this study was to investigate the effects of the loss of endogenous H2S production on myocardial ischemia/reperfusion (MI/R) injury in mice with genetic deficiency of CSE. Methods CSE KO and wild-type (WT) mice (n = 12–13 per group) were subjected to 45 min of MI and 24 h of R. Myocardial area-at-risk (AAR) per left ventricle (LV), infarct per AAR, INF/LV, and circulating troponin-I levels were measured. H2S sulfur levels were measured in tissue and blood using gas chromatography and chemiluminesence. Nitrite levels in plasma and tissue were measured by HPLC. Western blot analysis was performed for p-eNOS ser1177 and total eNOS. Results CSE KO mice exhibited significant reductions in H2S and sulfane sulfur in the heart and circulation compared to WT mice. In addition, CSE KO mice displayed a significant (p < 0.01) increase in myocardial infarct size (INF) per AAR compared to WT (62 ± 2% vs. 42 ± 3%). This exacerbation of MI/R injury in CSE KO mice was attenuated by 50% following acute H2S therapy with Na2S evidenced by significant reductions in myocardial infarct size and plasma troponin-I levels. Interestingly, baseline p-eNOSser1177 was significantly decreased in the CSE KO mice suggesting dysregulation of eNOS in the setting of H2S bioavailability. Furthermore, CSE KO mice displayed significant reductions in circulating and myocardial nitrite levels compared to WT. Summary and conclusion Decreases in H2S bioavailability attenuate eNOS function and NO bioavailability resulting in reductions in nitrite and increased MI/R injury. These data demonstrate the critical role of endogenous H2S on protection of the heart against MI/R injury and the regulation of NO production. Disclosure Nothing to disclose.
    Nitric Oxide. 31:S31.
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    ABSTRACT: Background Nitric oxide (NO) bioavailability is reduced in the setting of heart failure. Nitrite (NO2) is a critically important NO intermediate that is readily metabolized to NO during various pathological states. We have previously demonstrated that sodium nitrite (NaNO2) ameliorates acute myocardial ischemia/reperfusion (MI/R) injury when administered at reperfusion and pretreatment with NaNO2 preconditions the heart against MI/R injury. However, no evidence exists as to whether increasing NO bioavailability via increased NO2 therapy attenuates pressure overload induced heart failure following transverse aortic constriction. Methods and results Transverse aortic constriction (TAC) was performed in male C57/BL6J mice (n = 13 per group) at 10–12 weeks of age. NaNO2 (50 mg/L) or saline vehicle (VEH) was administered daily in the drinking water post-operative day 1 for 9 weeks. Two-dimensional echocardiography was performed at baseline and at 1, 3, 6, and 9 weeks post (TAC) to assess left ventricular dimensions and left ventricular ejection fraction (LVEF). We observed significantly increased circulating and cardiac NO2 and nitrosothiol levels in mice treated with oral NaNO2. NaNO2 (50 mg/L) significantly preserved LVEF and improved left ventricular LV dimensions (LVEDD/LVESD; 3.5/2.2 mm vs. 4.8/4.0 mm, p < 0.001) at 9 weeks when compared to VEH. In addition, circulating brain natriuretic peptide (BNP) levels were significantly (p < 0.05) attenuated in mice receiving NaNO2. Chronic NaNO2 therapy resulted in upregulation of the AKT–eNOS–nitric oxide–cGMP pathway and activation of MEK1/2 ERK pathway along with the attenuation of oxidative stress. Furthermore, in additional studies we observed significant preservation of cardiac function following TAC in cardiac specific eNOS transgenic mice (CS-eNOS Tg) with increased blood and heart NO2 and nitrosothiol levels. Conclusions These results demonstrate that oral NaNO2 therapy or cardiac restricted eNOS gene therapy significantly increases nitrite (NO2) bioavailability, NO bioavailability, and confers significant preservation of cardiac structure and function during heart failure following TAC induced pressure overload. Disclosure Nothing to disclose.
    Nitric Oxide. 31:S30.