α -Adrenergic Receptor Stimulation Produces Late Preconditioning Through Inducible Nitric Oxide Synthase in Mouse Heart

Tejero-Taldo, Isabel; Gursoy, Erdal; Zhao, Ting C.; Kukreja, Rakesh C.

doi:10.1006/jmcc.2001.1500

Cited by 49 publications

(40 citation statements)

References 29 publications

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“…Acute α 1 -AR inhibition of myocyte apoptosis is well documented (51)(52)(53)(54), and the mechanisms include activating Erk and inactivating BAD, stimulating adenosine production, increasing glucose metabolism, and reducing intracellular acidity (3,4). Besides these acute effects, α 1 -ARs chronically upregulate antiapoptotic factors, such as superoxide dismutase and iNOS (55,56). Similarly, preliminary DNA array experiments identify several genes related to apoptosis that are regulated significantly in α 1 -AR KO myocytes (P. Simpson et al, unpublished observations).…”

Section: Figurementioning

confidence: 94%

1-Adrenergic receptors prevent a maladaptive cardiac response to pressure overload

OʼConnell

Swigart²,

Rodrigo

et al. 2006

Journal of Clinical Investigation

130

139

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An α 1 -adrenergic receptor (α 1 -AR) antagonist increased heart failure in the Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT), but it is unknown whether this adverse result was due to α 1 -AR inhibition or a nonspecific drug effect. We studied cardiac pressure overload in mice with double KO of the 2 main α 1 -AR subtypes in the heart, α 1A (Adra1a) and α 1B (Adra1b). At 2 weeks after transverse aortic constriction (TAC), KO mouse survival was only 60% of WT, and surviving KO mice had lower ejection fractions and larger end-diastolic volumes than WT mice. Mechanistically, final heart weight and myocyte cross-sectional area were the same after TAC in KO and WT mice. However, KO hearts after TAC had increased interstitial fibrosis, increased apoptosis, and failed induction of the fetal hypertrophic genes. Before TAC, isolated KO myocytes were more susceptible to apoptosis after oxidative and β-AR stimulation, and β-ARs were desensitized. Thus, α 1 -AR deletion worsens dilated cardiomyopathy after pressure overload, by multiple mechanisms, indicating that α 1 -signaling is required for cardiac adaptation. These results suggest that the adverse cardiac effects of α 1 -antagonists in clinical trials are due to loss of α 1 -signaling in myocytes, emphasizing concern about clinical use of α 1 -antagonists, and point to a revised perspective on sympathetic activation in heart failure.

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Section: Figurementioning

confidence: 94%

1-Adrenergic receptors prevent a maladaptive cardiac response to pressure overload

OʼConnell

Swigart²,

Rodrigo

et al. 2006

Journal of Clinical Investigation

130

139

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“…We recently demonstrated that sildenafil up-regulated iNOS and eNOS in the intact murine myocardium, and delayed protection induced by this drug was completely abolished with 1400W, a selective inhibitor of iNOS (14). In addition, it is now well appreciated that various stimuli such as brief episodes of ischemia (35), endotoxin-derivatives (36), agonists of G protein-coupled receptors (37,38), and systemic hypoxia (39) induce delayed preconditioning in an iNOS-dependent manner. The present results suggest that the NOSdependent mechanism in sildenafil-induced protection plays a crucial role in the inhibition of apoptosis and necrosis in the cardiomyocytes also.…”

Section: Effect Of Sildenafil On Bcl-2 Expression In Inos-or Enosdefimentioning

confidence: 99%

Phosphodiesterase-5 Inhibitor Sildenafil Preconditions Adult Cardiac Myocytes against Necrosis and Apoptosis

Das

Xi²,

Kukreja

2005

Journal of Biological Chemistry

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320

276

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We investigated the effect of sildenafil in protection against necrosis or apoptosis in cardiomyocytes. Adult mouse ventricular myocytes were treated with sildenafil (1 or 10 M) for 1 h before 40 min of simulated ischemia (SI). Necrosis was determined by trypan blue exclusion and lactate dehydrogenase release following SI alone or plus 1 or 18 h of reoxygenation (RO). Apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated nick end labeling assay and mitochondrial membrane potential measured using a fluorescent probe 5,5 ,6,6 -tetrachloro-1,1 ,3,3 -tetraethylbenzimidazolyl-carbocyanine iodide (JC-1). Sildenafil reduced necrosis as indicated by decrease in trypan blue-positive myocytes and leakage of lactate dehydrogenase compared with untreated cells after either SI or SI-RO. The number of terminal deoxynucleotidyl transferase-mediated nick end labeling-positive myocytes or loss of JC-1 fluorescence following SI and 18 h of RO was attenuated in the sildenafil-treated group with concomitant inhibition of caspase 3 activity. An early increase in Bcl-2 to Bax ratio with sildenafil treatment was also observed in myocytes after SI-RO. The increase of Bcl-2 expression by sildenafil was inhibited by nitric-oxide synthase (NOS) inhibitor, L-nitro-amino-methyl-ester. The drug also enhanced mRNA and protein content of inducible NOS (iNOS) and endothelial NOS (eNOS) in the myocytes. Sildenafil-induced protection against necrosis and apoptosis was absent in the myocytes derived from iNOS knock-out mice and was attenuated in eNOS knock-out myocytes. The up-regulation of Bcl-2 expression by sildenafil was also absent in iNOS-deficient myocytes. Reverse transcription-PCR, Western blots, and immunohistochemical assay confirmed the expression of phosphodiesterase-5 in mouse cardiomyocytes. These data provide strong evidence for a direct protective effect of sildenafil against necrosis and apoptosis through NO signaling pathway. The results may have possible therapeutic potential in preventing myocyte cell death following ischemia/reperfusion.

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“…Several preconditioning strategies have been reported, including sublethal ischemia and pharmacological approaches (38,43,45). Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric ␣␤ transcription factor that mediates tissue responses to ischemiahypoxia (48).…”

mentioning

confidence: 99%

Activation of hypoxia-inducible factor-1 via prolyl-4 hydoxylase-2 gene silencing attenuates acute inflammatory responses in postischemic myocardium

Natarajan¹,

Salloum²,

Fisher³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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α -Adrenergic Receptor Stimulation Produces Late Preconditioning Through Inducible Nitric Oxide Synthase in Mouse Heart

Cited by 49 publications

References 29 publications

1-Adrenergic receptors prevent a maladaptive cardiac response to pressure overload

1-Adrenergic receptors prevent a maladaptive cardiac response to pressure overload

Phosphodiesterase-5 Inhibitor Sildenafil Preconditions Adult Cardiac Myocytes against Necrosis and Apoptosis

Activation of hypoxia-inducible factor-1 via prolyl-4 hydoxylase-2 gene silencing attenuates acute inflammatory responses in postischemic myocardium

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