Targeting of phospholamban by peroxynitrite decreases β-adrenergic stimulation in cardiomyocytes

Kohr, Mark J.; Wang, Honglan; Wheeler, Debra G.; Murugesan, V.; Zweíer, Jay L.; Ziolo, Mark T.

doi:10.1093/cvr/cvm018

Cited by 40 publications

(73 citation statements)

References 48 publications

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“…At this concentration, SIN-1 released 3 nmol L −1 min −1 of peroxynitrite over the same time course as our functional experiments. We previously determined that 200 μmol/L SIN-1 released 18 nmol L −1 min −1 of peroxynitrite [13].…”

Section: Peroxynitrite Production Resulting From Sin-1mentioning

confidence: 99%

“…Ventricular myocytes were isolated from PLB knockout (PLB −/− ) and their corresponding wildtype (WT, CF1) as previously described [13]. Briefly, hearts were excised from mice anesthetized with sodium pentobarbital.…”

Section: Cardiomyocyte Isolationmentioning

confidence: 99%

“…Electron paramagnetic resonance (EPR) spectroscopy with 1-hydroxy-3-carboxy-2,2,5,5-tetramethylpyrrolidine hydrochloride (CP-H; Alexis, Lausen, Switzerland) was used to measure the rate of peroxynitrite release from SIN-1 under our experimental conditions as previously described [13,20]. Briefly, EPR spectra were recorded using a quartz flat cell at room temperature with a Bruker ESP 300E spectrometer (Billerica, MA) operating at X-band with 100-KHz modulation frequency and a TM 110 cavity.…”

Section: Measurement Of Peroxynitrite Release Ratementioning

confidence: 99%

“…[Ca 2+ ] i transients and shortening were measured in isolated myocytes as previously described [13]. Briefly, isolated myocytes were loaded at 22° C with 10 μmol/L Fluo-4 AM (Molecular Probes, Eugene, OR) for 30 minutes.…”

Section: Simultaneous Measurement Of Cellular [Ca 2+ ] I Transient Anmentioning

confidence: 99%

“…For instance, numerous studies have shown high concentrations of peroxynitrite to be detrimental to myocardial contractility [10][11][12][13][14][15], while at low concentrations peroxynitrite appears to act as a positive inotropic agent [16][17][18]. However, the majority of these studies examined effects on basal contractility and did not address the effects of peroxynitrite as they relate to β-adrenergic responsiveness.…”

Section: Introductionmentioning

confidence: 99%

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Biphasic effect of SIN-1 is reliant upon cardiomyocyte contractile state

Kohr¹,

Wang²,

Wheeler³

et al. 2008

Free Radical Biology and Medicine

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Many studies have demonstrated a biphasic effect of peroxynitrite in the myocardium, but few studies have investigated this biphasic effect on β-adrenergic responsiveness and its dependence on contractile state. We have previously shown that high SIN-1 (source of peroxynitrite, 200 μmol/L) produced significant anti-adrenergic effects during maximal β-adrenergic stimulation in cardiomyocytes. In the current study, we hypothesize that the negative effects of high SIN-1 will be greatest during high contractile states, while the positive effects of low SIN-1 (10 μmol/L) will predominate during low contractility. Isolated murine cardiomyocytes were field stimulated at 1 Hz and [Ca 2+ ] i transients and shortening were recorded. Following submaximal ISO (β-adrenergic agonist, 0.01 μmol/L) stimulation, 200 μmol/L SIN-1 induced two distinct phenomena. Cardiomyocytes undergoing a large response to ISO showed a significant reduction in contractility, while cardiomyocytes exhibiting a modest response to ISO showed a further increase in contractility. Additionally, 10 μmol/L SIN-1 always increased contractility during low ISO stimulation, but had no effect during maximal ISO (1 μmol/L) stimulation. 10 μmol/L SIN-1 also increased basal contractility. Interestingly, SIN-1 only produced a contractile effect under one condition in phospholamban knockout cardiomyocytes, providing a potential mechanism for the biphasic effect of peroxynitrite. These results provide clear evidence for a biphasic effect of peroxynitrite, with high peroxynitrite modulating high levels of β-adrenergic responsiveness and low peroxynitrite regulating basal function and low levels of β-adrenergic stimulation.

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Section: Peroxynitrite Production Resulting From Sin-1mentioning

confidence: 99%

Section: Cardiomyocyte Isolationmentioning

confidence: 99%

Section: Measurement Of Peroxynitrite Release Ratementioning

confidence: 99%

Section: Simultaneous Measurement Of Cellular [Ca 2+ ] I Transient Anmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Biphasic effect of SIN-1 is reliant upon cardiomyocyte contractile state

Kohr¹,

Wang²,

Wheeler³

et al. 2008

Free Radical Biology and Medicine

Self Cite

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Nitric Oxide: Physiological Functions, Delivery, and Biomedical Applications

Andrabi,

Sharma,

Karan

et al. 2023

Advanced Science

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Nitric oxide (NO) is a gaseous molecule that has a central role in signaling pathways involved in numerous physiological processes (e.g., vasodilation, neurotransmission, inflammation, apoptosis, and tumor growth). Due to its gaseous form, NO has a short half‐life, and its physiology role is concentration dependent, often restricting its function to a target site. Providing NO from an external source is beneficial in promoting cellular functions and treatment of different pathological conditions. Hence, the multifaceted role of NO in physiology and pathology has garnered massive interest in developing strategies to deliver exogenous NO for the treatment of various regenerative and biomedical complexities. NO‐releasing platforms or donors capable of delivering NO in a controlled and sustained manner to target tissues or organs have advanced in the past few decades. This review article discusses in detail the generation of NO via the enzymatic functions of NO synthase as well as from NO donors and the multiple biological and pathological processes that NO modulates. The methods for incorporating of NO donors into diverse biomaterials including physical, chemical, or supramolecular techniques are summarized. Then, these NO‐releasing platforms are highlighted in terms of advancing treatment strategies for various medical problems.

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Influence of phosphodiesterases and cGMP on cAMP generation and on phosphorylation of phospholamban and troponin I by 5-HT4 receptor activation in porcine left atrium

Weninger

Maeyer

Lefebvre

2013

Naunyn-Schmiedeberg's Arch Pharmacol

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Our objective was to investigate the role of phosphodiesterase (PDE)3 and PDE4 and cGMP in the control of cAMP metabolism and of phosphorylation of troponin I (TnI) and phospholamban (PLB) when 5-HT 4 receptors are activated in pig left atrium. Electrically paced porcine left atrial muscles, mounted in organ baths, received stimulators of particulate guanylyl cyclase (pGC) or soluble guanylyl cyclase (sGC) and/or specific PDE inhibitors followed by 5-HT or the 5-HT 4 receptor agonist prucalopride. Muscles were freezeclamped at different moments of exposure to measure phosphorylation of the cAMP/protein kinase A targets TnI and PLB by immunoblotting and cAMP levels by enzyme immunoassay. Corresponding with the functional results, 5-HT only transiently increased cAMP content, but caused a less quickly declining phosphorylation of PLB and did not significantly change TnI phosphorylation. Under combined PDE3 and PDE4 inhibition, the 5-HT-induced increase in cAMP levels and PLB phosphorylation was enhanced and sustained, and TnI phosphorylation was now also increased. Responses to prucalopride per se and the influence thereupon of PDE3 and PDE4 inhibition were similar except that responses were generally smaller. Stimulation of pGC together with PDE4 inhibition increased 5-HT-induced PLB phosphorylation compared to 5-HT alone, consistent with functional responses. sGC stimulation hastened the fade of inotropic responses to 5-HT, while cAMP levels were not altered. PDE3 and PDE4 control the cAMP response to 5-HT 4 receptor activation, causing a dampening of downstream signalling. Stimulation of pGC is able to enhance inotropic responses to 5-HT by increasing cAMP levels, while sGC stimulation decreases contraction to 5-HT cAMP independently.

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Targeting of phospholamban by peroxynitrite decreases β-adrenergic stimulation in cardiomyocytes

Cited by 40 publications

References 48 publications

Biphasic effect of SIN-1 is reliant upon cardiomyocyte contractile state

Biphasic effect of SIN-1 is reliant upon cardiomyocyte contractile state

Nitric Oxide: Physiological Functions, Delivery, and Biomedical Applications

Influence of phosphodiesterases and cGMP on cAMP generation and on phosphorylation of phospholamban and troponin I by 5-HT4 receptor activation in porcine left atrium

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