Phosphoinositide-Dependent Kinase-1 and Protein Kinase C<i>δ</i>Contribute to Endothelin-1 Constriction and Elevated Blood Pressure in Intermittent Hypoxia

Webster, Bruce; Osmond, Jessica M.; Paredes, Daniel; DeLeon, Xavier A.; Jackson‐Weaver, Olan; Walker, Benjimen R.; Kanagy, Nancy L.

doi:10.1124/jpet.112.195412

Cited by 19 publications

(9 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, just like the complex or even conflicting reports on the role of PKC in mediating myocardial protection from ischemia (40), ET-1-PKC interactions are complex. However, recent and growing evidence suggests that PKCd may play the predominant role in ET-1-mediated constriction and blood pressure elevation (41,42). Consistent with these studies, we found that a PKCd-inhibitory peptide significantly attenuated ET-1-induced eNOS mitochondrial redistribution and preserved mitochondrial bioenergetics.…”

Section: Discussionsupporting

confidence: 90%

Endothelin-1 Induces a Glycolytic Switch in Pulmonary Arterial Endothelial Cells via the Mitochondrial Translocation of Endothelial Nitric Oxide Synthase

Sun

Kumar

Sharma

et al. 2014

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Recent studies have indicated that, during the development of pulmonary hypertension (PH), there is a switch from oxidative phosphorylation to glycolysis in the pulmonary endothelium. However, the mechanisms underlying this phenomenon have not been elucidated. Endothelin (ET)-1, an endothelial-derived vasoconstrictor peptide, is increased in PH, and has been shown to play an important role in the oxidative stress associated with PH. Thus, in this study, we investigated whether there was a potential link between increases in ET-1 and mitochondrial remodeling. Our data indicate that ET-1 induces the redistribution of endothelial nitric oxide synthase (eNOS) from the plasma membrane to the mitochondria in pulmonary arterial endothelial cells, and that this was dependent on eNOS uncoupling. We also found that ET-1 disturbed carnitine metabolism, resulting in the attenuation of mitochondrial bioenergetics. However, ATP levels were unchanged due to a compensatory increase in glycolysis. Further mechanistic investigations demonstrated that ET-1 mediated the redistribution of eNOS via the phosphorylation of eNOS at Thr495 by protein kinase C d. In addition, the glycolytic switch appeared to be dependent on mitochondrial-derived reactive oxygen species that led to the activation of hypoxia-inducible factor signaling. Finally, the cell culture data were confirmed in vivo using the monocrotaline rat model of PH. Thus, we conclude that ET-1 induces a glycolytic switch in pulmonary arterial endothelial cells via the redistribution of uncoupled eNOS to the mitochondria, and that preventing this event may be an approach for the treatment of PH.Keywords: mitochondrial bioenergetics; endothelial nitric oxide synthase uncoupling; protein kinase C d; peroxynitrite; superoxide Clinical RelevanceIt is becoming increasingly clear that the Warburg effect plays an important role in the development of pulmonary hypertension (PH). However, mechanisms underlying the glycolytic switch are unresolved. Our data demonstrate that endothelin-1, which is increased in PH, is capable of inducing aerobic glycolysis in pulmonary endothelial cells.Mitochondria are essential for energy metabolism through their ability to generate cellular ATP through oxidative phosphorylation. Increasing evidence suggests that mitochondrial remodeling is a critical event in a number of cardiovascular diseases, including pulmonary hypertension (PH) (1, 2). PH is a fatal disease characterized by pathologic vascular remodeling, which eventually leads to right ventricular failure and death. Several decades ago, Warburg (3) identified

show abstract

Section: Discussionsupporting

confidence: 90%

Endothelin-1 Induces a Glycolytic Switch in Pulmonary Arterial Endothelial Cells via the Mitochondrial Translocation of Endothelial Nitric Oxide Synthase

Sun

Kumar

Sharma

et al. 2014

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

show abstract

“…In addition, OSA can impact glycemic control in T2DM, although this relationship was not found in the current cohort (data not shown). Increased advanced glycation end products and alterations in protein kinase C signaling are common pathways by which OSA and hyperglycemia contribute to microvascular complications [ 42 , 43 ]. Through these multiple pathways, OSA could exert adverse effects on diabetes-related complications.…”

Section: Discussionmentioning

confidence: 99%

The Relationship between Diabetes-Related Complications and Obstructive Sleep Apnea in Type 2 Diabetes

Siwasaranond

Nimitphong

Manodpitipong

et al. 2018

Journal of Diabetes Research

View full text Add to dashboard Cite

This study explored the relationship between obstructive sleep apnea (OSA) and the presence of any diabetes-related complications in type 2 diabetes and whether this was mediated by hypertension. Secondly, the relationship between OSA severity and estimated glomerular filtration rate (eGFR) was investigated. A total of 131 patients participated. OSA was diagnosed using a home monitor, and severity was measured by apnea-hypopnea index (AHI) and oxygen desaturation index (ODI). OSA was found in 75.6% of the participants, 40.5% with moderate-to-severe degree. Any diabetes-related complications (retinopathy, neuropathy, nephropathy, or coronary artery disease) were present in 55.5%, and 70.2% of the participants had hypertension. Mediation analysis indicated that, compared to those with mild or no OSA, those with moderate-to-severe OSA were 3.05 times more likely to have any diabetes-related complications and that this relationship was mediated by the presence of hypertension. After adjusting for confounders, ODI (B = −0.036, p = 0.041), but not AHI, was significantly associated with lower eGFR. In conclusion, moderate-to-severe OSA was related to the presence of any diabetes-related complications in type 2 diabetes, and the relationship was mediated by hypertension. The severity of intermittent hypoxia was associated with lower eGFR. Whether OSA treatment will delay or reduce diabetes-related complications should be investigated.

show abstract

“…PKC is a multigene large family of serine/threonine kinases which plays important roles in signal transduction in health and disease, contributing to endothelial dysfunction, vascular permeability, angiogenesis, cell growth and apoptosis. Some studies indicated that PKCδ signaling pathway might be involved in ET-1-mediated constriction in mesenteric arteries in IH-exposed rats (Allahdadi et al 2008;Webster et al 2013). Nevertheless, in pulmonary vascular smooth muscle, IH could augment ET-1-induced vasoconstriction through a PKCβ-dependent signaling mechanism (Snow et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Endothelin-1-Mediated Mechanisms in the Carotid Body Modulates Cardiovascular Responses in Rats Exposed to Chronic Intermittent Hypoxia

Yang

et al. 2018

Int J Pept Res Ther

View full text Add to dashboard Cite

Chronic intermittent hypoxia (CIH), the main feature of obstructive sleep apnea (OSA), is associated with hypertension. The increased of carotid body (CB) sensitivity due to enhanced sympathetic efferent may be mainly responsible for the elevation of blood pressure. Accordingly, we studied this effect of Endothelin-1 (ET-1)-induced CB chemosensory response to CIH, as a vasoactive peptide expressed in CB. The purpose of this study was to investigate the mean arterial blood pressure (MAP) and renal sympathetic nerve activity (RSNA) responses in CIH group by injecting ET-1 to directly stimulate CB chemoreceptor. Furthermore, whether ET receptor-mediated PKC and p 38 MAPK signaling pathway was involved in CIHinduced CB activation was also studied. Male Sprague-Dawley rats were exposed to CIH (8 h/day for 3 weeks) and the MAP and RSNA were recorded in CIH rats and Sham rats. Our results demonstrated that ET-1-induced MAP and RSNA increase were mainly mediated by ET A receptor activation in CB chemosensory after CIH exposure. Moreover, P 38 MAPK and PKC signaling pathway might be involved in ET-1-induced increase of MAP and RSNA in CIH group, which provided a potential therapeutic target of OSA.

show abstract

Phosphoinositide-Dependent Kinase-1 and Protein Kinase CδContribute to Endothelin-1 Constriction and Elevated Blood Pressure in Intermittent Hypoxia

Cited by 19 publications

References 26 publications

Endothelin-1 Induces a Glycolytic Switch in Pulmonary Arterial Endothelial Cells via the Mitochondrial Translocation of Endothelial Nitric Oxide Synthase

Endothelin-1 Induces a Glycolytic Switch in Pulmonary Arterial Endothelial Cells via the Mitochondrial Translocation of Endothelial Nitric Oxide Synthase

The Relationship between Diabetes-Related Complications and Obstructive Sleep Apnea in Type 2 Diabetes

Endothelin-1-Mediated Mechanisms in the Carotid Body Modulates Cardiovascular Responses in Rats Exposed to Chronic Intermittent Hypoxia

Contact Info

Product

Resources

About