The ductus arteriosus (DA) is a fetal artery that allows blood ejected from the right ventricle to bypass the pulmonary circulation in utero. At birth, functional closure of the DA is initiated within minutes by O2-induced vasoconstriction. Functional closure (vasoconstriction) stops right to left shunting of blood and promotes anatomical closure. Failure of these processes leads to persistent ductus arteriosus, a common form of congenital heart disease in premature infants. During the first 5 years of this grant we showed that the DA's O2- sensing pathway consists of a sensor (the mitochondrial electron transport chain), which produces a diffusible mediator (H2O2), that inhibits voltage-gated K+ channels, such as Kv1.5. At birth, O2-induced increases in mitochondrial H2O2 in DA smooth muscle cells (DASMC) promote constriction by several mechanisms: Kv channel inhibition, direct activation of O2-sensitive calcium channels and rho kinase activation. Moreover, preterm DASMC are relatively deficient in these mechanisms, explaining the prevalence of persistent DA in preterm DA. This renewal focuses on a discovery made during a search for splice variants of Kv1.5 in human DASMC. We found a novel K+ channel, Human Oxygen-Sensitive K+ channel (HOSK), that when heterologously expressed creates a current that is voltage-gated, displays K+ specificity (Rb>K>>Cs>Na), and is 4- aminopyridine sensitive. HOSK appears to contribute to the resting membrane potential in human DASMC. HOSK siRNA reduces the O2-sensitive current in human DASMC. HOSK cDNA corresponds to a 3.0 kb neuronal, expressed sequence tag (EST) and has an unusual coding mechanism. HOSK and collagen 12(I) have identical mRNA with the much smaller 21 kDa HOSK resulting from initiation of translation at an internal ribosomal entry site (IRES). In silico modeling suggests that HOSK may have four hydrophobic domains (HD), a unique K+ selectivity filter (GVL, rather than the typical GYG amino acid sequence) and a variant voltage sensor. Phylogenetic analysis suggests HOSK originated in amniotes. In this proposal, the relative importance of HOSK versus canonical O2-sensitive voltage-gated K+ channels, Kv1.5 and Kv2.1, will be compared in term human DA, and two models of impaired O2 constriction: preterm rabbit DA and ionically remodeled human DA.
Aim 1 : HOSK is a novel K+ channel, arising independent of the canonical K+ channel family.
Aim 2 : HOSK contributes to DA constriction and augmenting HOSK expression will enhance O2- constriction in preterm rabbit DA and ionically remodeled human DA.
Aim 3 : HIF-11 shifts translation of the collagen gene away from HOSK toward collagen 21(1). HOSK, hidden by its complex encoding mechanism and unique structure, may offer a new explanation for how O2 causes constriction and will shed light on the link between constriction and fibrous obliteration of the DA. Since HOSK may have arisen independent of the canonical K+ channel family, exploring its structure-function relationship will extend our fundamental knowledge K+ channels.

Public Health Relevance

With the first breath of life, the ductus arteriosus (DA) constricts in response to increased oxygen, forcing blood to the baby's newly expanded lungs. Failure of DA closure (persistent DA) is a common form of congenital heart disease. We discovered that the DA senses oxygen using a mitochondrial sensor, which generates hydrogen peroxide, thereby inhibiting voltage-gated K+ channels as oxygen increases, and causing DA constriction. This renewal grant focuses on Human Oxygen-Sensitive K+ channel (HOSK), a novel K+ channel, which we discovered in human DA. Hidden by a complex encoding mechanism and unique structure, HOSK promises new understanding of K+ channel structure-function relationships and may link constriction and fibrous obliteration of the DA.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071115-09
Application #
8279157
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Kaltman, Jonathan R
Project Start
2002-07-01
Project End
2012-11-30
Budget Start
2012-05-01
Budget End
2012-11-30
Support Year
9
Fiscal Year
2012
Total Cost
$390,000
Indirect Cost
$140,000
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Hemnes, Anna R; Trammell, Aaron W; Archer, Stephen L et al. (2015) Peripheral blood signature of vasodilator-responsive pulmonary arterial hypertension. Circulation 131:401-9; discussion 409
Ryan, John J; Archer, Stephen L (2014) The right ventricle in pulmonary arterial hypertension: disorders of metabolism, angiogenesis and adrenergic signaling in right ventricular failure. Circ Res 115:176-88
Hong, Zhigang; Cabrera, J├ęsus A; Mahapatra, Saswati et al. (2014) Activation of the EGFR/p38/JNK pathway by mitochondrial-derived hydrogen peroxide contributes to oxygen-induced contraction of ductus arteriosus. J Mol Med (Berl) 92:995-1007
Samant, Sadhana A; Zhang, Hannah J; Hong, Zhigang et al. (2014) SIRT3 deacetylates and activates OPA1 to regulate mitochondrial dynamics during stress. Mol Cell Biol 34:807-19
Sharp, Willard W; Fang, Yong Hu; Han, Mei et al. (2014) Dynamin-related protein 1 (Drp1)-mediated diastolic dysfunction in myocardial ischemia-reperfusion injury: therapeutic benefits of Drp1 inhibition to reduce mitochondrial fission. FASEB J 28:316-26
Kim, Gene H; Ryan, John J; Archer, Stephen L (2013) The role of redox signaling in epigenetics and cardiovascular disease. Antioxid Redox Signal 18:1920-36
Piao, Lin; Sidhu, Vaninder K; Fang, Yong-Hu et al. (2013) FOXO1-mediated upregulation of pyruvate dehydrogenase kinase-4 (PDK4) decreases glucose oxidation and impairs right ventricular function in pulmonary hypertension: therapeutic benefits of dichloroacetate. J Mol Med (Berl) 91:333-46
Piao, Lin; Fang, Yong-Hu; Parikh, Kishan et al. (2013) Cardiac glutaminolysis: a maladaptive cancer metabolism pathway in the right ventricle in pulmonary hypertension. J Mol Med (Berl) 91:1185-97
Ryan, John J; Marsboom, Glenn; Fang, Yong-Hu et al. (2013) PGC1*-mediated mitofusin-2 deficiency in female rats and humans with pulmonary arterial hypertension. Am J Respir Crit Care Med 187:865-78
Prochaska, Micah T; Bergl, Paul A; Patel, Amit R et al. (2013) Atrioventricular heart block and syncope coincident with diagnosis of systemic lupus erythematosus. Can J Cardiol 29:1330.e5-1330.e7

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