Hyperoxia-induced hypertrophy and ion channel remodeling in left ventricle

Abstract

In the present study we investigated cardiac hypertrophy and cardiac complications in mice subjected to hyperoxia. Results demonstrate that there is a significant increase in average heart weight to tibia length (22%) in mice subjected to hyperoxia treatment vs. normoxia. Functional assessment was performed in mice subjected to hyperoxic treatment, and results demonstrate impaired cardiac function with decreased cardiac output and heart rate. Staining of transverse cardiac sections clearly demonstrates an increase in the cross-sectional area from hyperoxic hearts compared with control hearts. Quantitative real-time RT-PCR and Western blot analysis indicated differential mRNA and protein expression levels between hyperoxia-treated and control left ventricles for ion channels including Kv4.2 (Ϫ2 Ϯ 0.08), Kv2.1 (2.54 Ϯ 0.48), and Scn5a (1.4 Ϯ 0.07); chaperone KChIP2 (Ϫ1.7 Ϯ 0.06); transcriptional factors such as GATA4 (Ϫ1.5 Ϯ 0.05), Irx5 (5.6 Ϯ 1.74), NFB1 (4.17 Ϯ 0.43); hypertrophy markers including MHC-6 (2.17 Ϯ 0.36) and MHC-7 (4.62 Ϯ 0.76); gap junction protein Gja1 (4.4 Ϯ 0.8); and microRNA processing enzyme Drosha (4.6 Ϯ 0.58). Taken together, the data presented here clearly indicate that hyperoxia induces left ventricular remodeling and hypertrophy and alters the expression of Kv4.2 and MHC6/7 in the heart. ion channel regulation; hyperoxia; heart; hypertrophy; potassium channel; redox PATIENTS in critical or intensive care units (ICU) with acute lung injury or cardiac disease are often administered 100% O 2 for treatment. Recent studies indicate that hyperoxia induces cardiac injury due to dysfunctional lung and compromised pulmonary functioning (37), even though the exact nature of this problem remains unknown. Here, we evaluated changes in expression of the ion channel and key transcriptional factors in the heart that occur with hyperoxia and likely play a role in cardiovascular remodeling.Potassium channels and their auxiliary subunits such as potassium channel interacting protein-2 (KChIP2) are abundantly expressed in the heart (5, 7, 35). It is established that the potassium channels Kv4.2 and Kv1.5 are responsive to oxygen changes (29, 39). In the present study, we investigate whether hyperoxia alters expression of the transcription factors Irx5 and Mef2c, which are implicated to play a direct role in regulating Kv4.2 expression (7,15,22). Cardiac-specific markers used to identify hypertrophy and transcriptional changes (9, 22) were also evaluated by assessing myosin heavy chain-6, and -7 (MHC6, MHC7), zinc finger transcription factor (GATA4), histone-lysine N-methyltransferase (Ezh2), and Six-1 expression levels with hyperoxia.Key inflammatory mediators such as TNF␣ and NFB are central regulators or master switches for many pathological processes (10,20,30). Recent evidence indicates that NFB regulates KChIP2, which in turn regulates Kv4.2 expression (26). Therefore we assessed the levels of Kv4.2, KChIP2, and NFB in the mouse heart subjected to hyperoxia. We hypothesized that hyperoxia induces cardi...

Deletion of Kvβ1.1 subunit leads to electrical and haemodynamic changes causing cardiac hypertrophy in female murine hearts

“…Sections were stained with Haematoxylin and Eosin for histological examination (Panguluri et al 2013 b ). …”

“…M-Mode imaging from the short axis of the left ventricle (LV), using the papillary muscles for reference, was used to obtain measurements of LV posterior and anterior wall (LVPW and LVAW) thicknesses as well as LV internal dimensions in diastole and systole (LVIDd and LVIDs). Fractional shortening (FS%) and ejection fraction (EF%) were calculated as previously described (Panguluri et al 2013 b ). For measurment of systolic flow, pulse wave (PW) Doppler was used to image the ascending aortic arch as well as the pulmonary artery in long axis to obtain mean flow velocity and the velocity–time integral of both the aortic arch and the pulmonary artery.…”

“…Complimentary DNA (cDNA) from total RNA was synthesized, and quantitative real-time PCR (qRT-PCR) analysis was performed to measure the mRNA expression of hypertrophic markers, including Myosin Heavy chain alpha (MHC α ), Myosin Heavy Chain Beta (MHC β ), GATA-Binding Protein 6 (GATA6), Bone Morphogenetic Protein 10 (BMP10) and Phosphatidylinositol-4,5-Bisphosphate 3-Kinase (PI3K). All the cDNA synthesis and qRT-PCR procedures were performed as described previously (Panguluri et al 2013 b ). The expression of mouse HPRT transcript was used as an endogenous reference.…”

Proteomic analysis of mitochondrial proteins in the guinea pig heart following long-term normobaric hyperoxia

“…TPM1 and MYL2 were overexpressed only in NBO group; while the latter protein was upregulated by both hyperoxic treatments. Increased levels of myosin heavy chain-6 and 7 have been found in mouse heart after 72 h hyperoxia treatment [9], alterations in other proteins associated with cardiac contractility were not published. All overexpressed proteins are involved in the regulation of cardiac myocyte contraction.…”

“…Several animal and clinical studies have shown that hyperoxia induces vasoconstriction in the brain, heart, and other tissues [2,7,8]. Hyperoxia can also exacerbate cardiovascular performance and induce cardiac hypertrophy and arrhythmias [9,10], for review see [11]. Therefore, medical uses of NBO or HBO treatments are controversial, and current guidelines recommend limiting exposure to excessively high oxygen concentrations [12].…”