Receptor-activating peptides distinguish thrombin receptor (PAR-1) and protease activated receptor 2 (PAR-2) mediated hemodynamic responses in vivo

Cheung, Wai-man; Andrade‐Gordon, Patricia; Derian, Claudia K.; Damiano, Bruce P.

doi:10.1139/cjpp-76-1-16

Cited by 30 publications

(26 citation statements)

References 41 publications

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“…Consistently with previously published data, PAR-1 deficiency had no significant effect on the baseline diastolic and systolic BP (Supplement 1) [24, 25]. Interestingly, infusion of Ang II at the concentration of 600ng/kg/min caused only modest but not statistically significant increase of BP in both WT and PAR-1 −/− mice measured at day 7 and 28 after initiation of infusion (Supplement 1).…”

Section: Resultssupporting

confidence: 90%

“…These studies suggest that PAR-1-dependent vasoregulation may be cell/tissue specific. In mice, activation of PAR-1 with agonist peptide results in a biphasic BP response in which there is a rapid and transient hypotension followed by sustained HTN, presumably via activation of PAR-1 on smooth muscle cells [24]. Unstressed PAR-1 −/− mice exhibit no obvious abnormalities in baseline BP compared to PAR-1 +/+ mice [24, 25].…”

Section: Introductionmentioning

confidence: 99%

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Protease-Activated Receptor 1 Contributes to Angiotensin II-Induced Cardiovascular Remodeling and Inflammation

Antoniak

Cardenas²,

Buczek³

et al. 2016

Cardiology

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Background: Angiotensin II (Ang II) plays an important role in cardiovascular disease. It also leads to the activation of coagulation. The coagulation protease thrombin induces cellular responses by activating protease-activated receptor 1 (PAR-1). We investigated whether PAR-1 contributes to Ang II-induced cardiovascular remodeling and inflammation. Methods and Results: PAR-1^+/+ (wild-type; WT) and PAR-1^-/- mice were infused with Ang II (600 ng/kg/min) for up to 4 weeks. In WT mice, this dose of Ang II did not cause a significant increase in blood pressure but it did cause pathological changes in both the aorta and the heart. Ang II infusion resulted in vascular remodeling of the aorta, demonstrated by a significant increase in medial wall thickening and perivascular fibrosis. Importantly, both parameters were significantly attenuated by PAR-1 deficiency. Furthermore, perivascular fibrosis around coronary vessels was reduced in Ang II-treated PAR-1^-/- mice compared to WT mice. In addition, PAR-1 deficiency significantly attenuated Ang II induction of inflammatory cytokines and profibrotic genes in the aortas compared to WT mice. Finally, PAR-1 deficiency had no effect on Ang II-induced heart hypertrophy. However, the heart function measured by fractional shortening was less impaired in PAR-1^-/- mice than in WT mice. Conclusion: Our data indicate that PAR-1 plays a significant role in cardiovascular remodeling mediated by a blood pressure-independent action of Ang II.

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Section: Resultssupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Protease-Activated Receptor 1 Contributes to Angiotensin II-Induced Cardiovascular Remodeling and Inflammation

Antoniak

Cardenas²,

Buczek³

et al. 2016

Cardiology

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“…The effects of PAR activators on cardiovascular responses have been investigated in intact animals. In mice, intravenous injection of PAR 1 -selective AP causes a rapid and sustained hypotension, which is not NO mediated (47). Similarly, in rats and mice, PAR 2 activators cause hypotension by NO-dependent and -independent mechanisms, which can be followed by a reflex hypertension (52).…”

Section: Par Signaling To the Vesselsmentioning

confidence: 98%

Protease-Activated Receptors: Contribution to Physiology and Disease

Ossovskaya

Bunnett

2004

Physiological Reviews

995

1,103

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Proteases acting at the surface of cells generate and destroy receptor agonists and activate and inactivate receptors, thereby making a vitally important contribution to signal transduction. Certain serine proteases that derive from the circulation (e.g., coagulation factors), inflammatory cells (e.g., mast cell and neutrophil proteases), and from multiple other sources (e.g., epithelial cells, neurons, bacteria, fungi) can cleave protease-activated receptors (PARs), a family of four G protein-coupled receptors. Cleavage within the extracellular amino terminus exposes a tethered ligand domain, which binds to and activates the receptors to initiate multiple signaling cascades. Despite this irreversible mechanism of activation, signaling by PARs is efficiently terminated by receptor desensitization (receptor phosphorylation and uncoupling from G proteins) and downregulation (receptor degradation by cell-surface and lysosomal proteases). Protease signaling in tissues depends on the generation and release of proteases, availability of cofactors, presence of protease inhibitors, and activation and inactivation of PARs. Many proteases that activate PARs are produced during tissue damage, and PARs make important contributions to tissue responses to injury, including hemostasis, repair, cell survival, inflammation, and pain. Drugs that mimic or interfere with these processes are attractive therapies: selective agonists of PARs may facilitate healing, repair, and protection, whereas protease inhibitors and PAR antagonists can impede exacerbated inflammation and pain. Major future challenges will be to understand the role of proteases and PARs in physiological control mechanisms and human diseases and to develop selective agonists and antagonists that can be used to probe function and treat disease.

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“…However, the effect of PAR-2 on peripheral sympathetic activity, which regulates peripheral vascular resistance, is not fully understood. According to previous reports, hypotension induced by PAR-2 activation is maintained for around 2–3 min, and the ganglion-blocking agent chlorisondamine significantly increases the duration of hypotension induced by PAR-2 activation, suggesting that PAR-2-induced hypotension may be maintained by modulating peripheral sympathetic tone ( Cheung et al, 1998 ; Cicala et al, 2001 ; Emilsson et al, 1999 ). However, a detailed mechanism for PAR-2 induced suppression of peripheral sympathetic outflow has not yet been elucidated.…”

Section: Introductionmentioning

confidence: 63%

“…Recently, it has been reported that PAR-2 is highly expressed in endothelial cells and vascular smooth muscle, suggesting a crucial role in regulating vascular tone ( al-Ani et al, 1995 ; Hollenberg et al, 1996 ; Magazine et al, 1996 ; Saifeddine et al, 1996 ). In fact, PAR-2 activation by receptor-activating peptides decreases blood pressure in anesthetized rats or mice in vivo ( Cheung et al, 1998 ; Cicala et al, 1999 ; 2001 ; Damiano et al, 1999 ; Emilsson et al, 1997 ; Kawabata et al, 2003 ). This hypotension is only partially inhibited by the nitric oxide synthase inhibitor, L-NAME, suggesting that a nitric oxide (NO)-independent mechanism as well as a NO-dependent mechanism are involved in hypotension induced by PAR-2 activation ( Cicala et al, 2001 ; Emilsson et al, 1997 ).…”

Section: Introductionmentioning

confidence: 99%

Protease-Activated Receptor 2 Activation Inhibits N-Type Ca2+ Currents in Rat Peripheral Sympathetic Neurons

Kim¹,

Ahn²,

Kim³

et al. 2014

Molecules and Cells

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The protease-activated receptor (PAR)-2 is highly expressed in endothelial cells and vascular smooth muscle cells. It plays a crucial role in regulating blood pressure via the modulation of peripheral vascular tone. Although several mechanisms have been suggested to explain PAR-2-induced hypotension, the precise mechanism remains to be elucidated. To investigate this possibility, we investigated the effects of PAR-2 activation on N-type Ca2+ currents (ICa-N) in isolated neurons of the celiac ganglion (CG), which is involved in the sympathetic regulation of mesenteric artery vascular tone. PAR-2 agonists irreversibly diminished voltage-gated Ca2+ currents (ICa), measured using the patch-clamp method, in rat CG neurons, whereas thrombin had little effect on ICa. This PAR-2-induced inhibition was almost completely prevented by ω-CgTx, a potent N-type Ca2+ channel blocker, suggesting the involvement of N-type Ca2+ channels in PAR-2-induced inhibition. In addition, PAR-2 agonists inhibited ICa–N in a voltage-independent manner in rat CG neurons. Moreover, PAR-2 agonists reduced action potential (AP) firing frequency as measured using the current-clamp method in rat CG neurons. This inhibition of AP firing induced by PAR-2 agonists was almost completely prevented by ω-CgTx, indicating that PAR-2 activation may regulate the membrane excitability of peripheral sympathetic neurons through modulation of N-type Ca2+ channels. In conclusion, the present findings demonstrate that the activation of PAR-2 suppresses peripheral sympathetic outflow by modulating N-type Ca2+ channel activity, which appears to be involved in PAR-2-induced hypotension, in peripheral sympathetic nerve terminals.

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Receptor-activating peptides distinguish thrombin receptor (PAR-1) and protease activated receptor 2 (PAR-2) mediated hemodynamic responses in vivo

Cited by 30 publications

References 41 publications

Protease-Activated Receptor 1 Contributes to Angiotensin II-Induced Cardiovascular Remodeling and Inflammation

Protease-Activated Receptor 1 Contributes to Angiotensin II-Induced Cardiovascular Remodeling and Inflammation

Protease-Activated Receptors: Contribution to Physiology and Disease

Protease-Activated Receptor 2 Activation Inhibits N-Type Ca2+ Currents in Rat Peripheral Sympathetic Neurons

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