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Papers by vishal yadav

Journal of Vascular Research, 2008

Background-Hypoxia causes heterogeneous contractile responses in resistance and conduit pulmonary... more Background-Hypoxia causes heterogeneous contractile responses in resistance and conduit pulmonary as well as systemic (mesenteric) artery smooth muscle cells (RPASMCs, CPASMCs and MASMCs), but the underlying mechanisms are largely unknown. In this study, we aimed to investigate whether the gene expression and functional activity of ryanodine receptors (RyRs) would be different in these 3 cell types.

Free Radical Biology and Medicine, 2011

This study was designed to determine whether: (1) hypoxia could directly affect ROS production in... more This study was designed to determine whether: (1) hypoxia could directly affect ROS production in isolated mitochondria and mitochondrial complex III from pulmonary artery smooth muscle cells (PASMCs), and (2) Rieske iron-sulfur protein in the complex III might mediate hypoxic ROS production, leading to hypoxic pulmonary vasoconstriction (HPV). Our data, for the first time, demonstrate that hypoxia significantly enhances ROS production, measured by the standard ROS indicator dichlorodihydrofluorescein/diacetate, in isolated mitochondria from PASMCs. Studies using the newly-developed, specific ROS biosensor pHyPer have found that hypoxia increases mitochondrial ROS generation as well in isolated PASMCs. The hypoxic ROS production has also been observed in isolated complex III. Rieske iron-sulfur protein silencing using siRNAs abolishes the hypoxic ROS formation in isolated PASM complex III, mitochondria and cells, while Rieske iron-sulfur protein overexpression produces the opposite effect. Rieske iron-sulfur protein silencing inhibits the hypoxic increase in [Ca 2+ ] i in PASMCs and hypoxic vasoconstriction in isolated PAs. These findings together provide novel evidence that mitochondria are the direct hypoxic targets in PASMCs, in which Rieske iron-sulfur protein in the complex III may serve as an essential, primary molecule that mediates the hypoxic ROS generation, leading to an increase in [Ca 2+ ] i in PASMCs and HPV.

Antioxidants & Redox Signaling, 2010

Here we attempted to test a novel hypothesis that hypoxia may induce Ca 2+ release through reacti... more Here we attempted to test a novel hypothesis that hypoxia may induce Ca 2+ release through reactive oxygen species (ROS)-mediated dissociation of FK506-binding protein 12.6 (FKBP12.6) from ryanodine receptors (RyRs) on the sarcoplasmic reticulum (SR) in pulmonary artery smooth muscle cells (PASMCs). The results reveal that hypoxic exposure significantly decreased the amount of FKBP12.6 on the SR of PAs and increased FKBP12.6 in the cytosol. The colocalization of FKBP12.6 with RyRs was decreased in intact PASMCs. Pharmacological and genetic inhibition of intracellular ROS generation prevented hypoxia from decreasing FKBP12.6 on the SR and increasing FKBP12.6 in the cytosol. Exogenous ROS (H 2 O 2 ) reduced FKBP12.6 on the SR and augmented FKBP12.6 in the cytosol. Oxidized FKBP12.6 was absent on the SR from PAs pretreated with and without hypoxia, but it was present with a higher amount in the cytosol from PAs pretreated with than without hypoxia. Hypoxia and H 2 O 2 diminished the association of FKBP12.6 from type 2 RyRs (RyR2). The activity of RyRs was increased in PAs pretreated with hypoxia or H 2 O 2 . FKBP12.6 removal enhanced, whereas RyR2 gene deletion blocked the hypoxic increase in [Ca 2+ ] i in PASMCs. Collectively, we conclude that hypoxia may induce Ca 2+ release by causing ROS-mediated dissociation of FKBP12.6 from RyR2 in PASMCs. Antioxid. Redox Signal. 14, 37-47.

Proceedings of The National Academy of Sciences, 2009