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Related Concept Videos

Treatment for Pulmonary Arterial Hypertension: Endothelin Receptor Antagonists01:18

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Endothelins (ETs) are potent vasoactive peptides critical in the human body's various physiological and pathological processes. One of the most promising therapeutic strategies for treating pulmonary arterial hypertension (PAH) involves counteracting the effects of these endothelins using a class of drugs known as endothelin receptor antagonists.
ETs are synthesized through a complex sequence of enzymatic steps, primarily involving an enzyme referred to as endothelin-converting enzyme...
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Endothelial Dysfunction Following Enhanced TMEM16A Activity in Human Pulmonary Arteries.

Davor Skofic Maurer1, Diana Zabini1,2, Chandran Nagaraj2

  • 1Otto Loewi Research Center, Medical University of Graz, Neue Stiftingtalstraße 6, 8010 Graz, Austria.

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Increased calcium-activated chloride channel (CaCC) TMEM16A activity in pulmonary arterial endothelial cells (PAECs) drives endothelial dysfunction in pulmonary arterial hypertension (PAH). This dysfunction involves altered calcium signaling and reduced nitric oxide production, contributing to PAH pathogenesis.

Keywords:
Ano1TMEM16AangiogenesisbenzbromaroneeNOS uncouplingendothelial dysfunctionintracellular calciummetabolic switchpulmonary endothelial cellspulmonary hypertension

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Area of Science:

  • Cardiovascular Biology
  • Molecular Medicine
  • Vascular Physiology

Background:

  • Endothelial dysfunction is a key feature of vascular diseases like pulmonary arterial hypertension (PAH).
  • While ion channel changes are implicated in PAH, the role of calcium-activated chloride channels (CaCC), particularly TMEM16A, in pulmonary arterial endothelial cells (PAECs) is understudied.
  • TMEM16A's contribution to idiopathic PAH (IPAH) pathogenesis in smooth muscle cells is known, but its role in endothelial cells is less understood.

Purpose of the Study:

  • To investigate the role of TMEM16A in the homeostasis of healthy human PAECs.
  • To determine the impact of enhanced TMEM16A activity on endothelial dysfunction in the context of IPAH.
  • To elucidate the downstream signaling pathways affected by elevated TMEM16A in PAECs.

Main Methods:

  • Whole-cell patch-clamp recordings to assess TMEM16A activity in IPAH PAECs.
  • Adenoviral-mediated TMEM16A overexpression in healthy primary human PAECs in vitro.
  • Ex vivo studies using human pulmonary arteries to evaluate functional consequences.
  • Analysis of calcium dynamics, eNOS activity, nitric oxide production, PAEC proliferation, wound healing, tube formation, and acetylcholine-mediated relaxation.

Main Results:

  • TMEM16A activity was enhanced in PAECs from IPAH patients.
  • Increased TMEM16A activity in healthy PAECs led to altered calcium dynamics and reduced eNOS activity.
  • Elevated TMEM16A impaired PAEC proliferation, wound healing, tube formation, and acetylcholine-mediated relaxation.
  • Nitric oxide production was decreased under conditions of heightened TMEM16A activity.

Conclusions:

  • Increased TMEM16A activity in the cell membrane of human PAECs contributes to endothelial dysfunction in PAH.
  • The ERK1/2 pathway is proposed as a key mediator affected by elevated TMEM16A activity, leading to pathological changes.
  • Targeting TMEM16A in PAECs presents a potential therapeutic strategy for PAH.