scholarly journals Beneficial effects of γ-aminobutyric acid on right ventricular pressure and pulmonary vascular remodeling in experimental pulmonary hypertension

Life Sciences ◽  
2012 ◽  
Vol 91 (13-14) ◽  
pp. 693-698 ◽  
Author(s):  
Rie Suzuki ◽  
Rumi Maehara ◽  
Shuhei Kobuchi ◽  
Ryosuke Tanaka ◽  
Mamoru Ohkita ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Aminobutyric Acid ◽  
Ventricular Pressure ◽  
Pulmonary Vascular Remodeling ◽  
Beneficial Effects

Therapeutic hypercapnia prevents chronic hypoxia-induced pulmonary hypertension in the newborn rat

2006 ◽  
Vol 291 (5) ◽  
pp. L912-L922 ◽  
Author(s):  
Crystal Kantores ◽  
Patrick J. McNamara ◽  
Lilian Teixeira ◽  
Doreen Engelberts ◽  
Prashanth Murthy ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Antioxidant Properties ◽  
Ventricular Performance ◽  
Pulmonary Vascular Remodeling ◽  
Beneficial Effects ◽  
Arterial Resistance ◽  
Pulmonary Arterial

Induction of hypercapnia by breathing high concentrations of carbon dioxide (CO2) may have beneficial effects on the pulmonary circulation. We tested the hypothesis that exposure to CO2 would protect against chronic pulmonary hypertension in newborn rats. Atmospheric CO2 was maintained at <0.5% (normocapnia), 5.5%, or 10% during exposure from birth for 14 days to normoxia (21% O2) or moderate hypoxia (13% O2). Pulmonary vascular and hemodynamic abnormalities in animals exposed to chronic hypoxia included increased pulmonary arterial resistance, right ventricular hypertrophy and dysfunction, medial thickening of pulmonary resistance arteries, and distal arterial muscularization. Exposure to 10% CO2 (but not to 5.5% CO2) significantly attenuated pulmonary vascular remodeling and increased pulmonary arterial resistance in hypoxia-exposed animals ( P < 0.05), whereas both concentrations of CO2 normalized right ventricular performance. Exposure to 10% CO2 attenuated increased oxidant stress induced by hypoxia, as quantified by 8-isoprostane content in the lung, and prevented upregulation of endothelin-1, a critical mediator of pulmonary vascular remodeling. We conclude that hypercapnic acidosis has beneficial effects on pulmonary hypertension and vascular remodeling induced by chronic hypoxia, which we speculate derives from antioxidant properties of CO2 on the lung and consequent modulating effects on the endothelin pathway.

scholarly journals The Short-Chain Fatty Acid Butyrate Attenuates Pulmonary Vascular Remodeling and Inflammation in Hypoxia-Induced Pulmonary Hypertension

2021 ◽  
Vol 22 (18) ◽  
pp. 9916
Author(s):  
Vijaya Karoor ◽  
Derek Strassheim ◽  
Timothy Sullivan ◽  
Alexander Verin ◽  
Nagavedi S. Umapathy ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Protective Effect ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Histone H3 ◽  
Systolic Pressure ◽  
Right Heart Failure ◽  
Sprague Dawley ◽  
Pulmonary Vascular Remodeling ◽  
Ventricular Systolic Pressure

Pulmonary hypertension (PH) is a progressive cardiovascular disorder in which local vascular inflammation leads to increased pulmonary vascular remodeling and ultimately to right heart failure. The HDAC inhibitor butyrate, a product of microbial fermentation, is protective in inflammatory intestinal diseases, but little is known regarding its effect on extraintestinal diseases, such as PH. In this study, we tested the hypothesis that butyrate is protective in a Sprague–Dawley (SD) rat model of hypoxic PH. Treatment with butyrate (220 mg/kg intake) prevented hypoxia-induced right ventricular hypertrophy (RVH), hypoxia-induced increases in right ventricular systolic pressure (RVSP), pulmonary vascular remodeling, and permeability. A reversal effect of butyrate (2200 mg/kg intake) was observed on elevated RVH. Butyrate treatment also increased the acetylation of histone H3, 25–34 kDa, and 34–50 kDa proteins in the total lung lysates of butyrate-treated animals. In addition, butyrate decreased hypoxia-induced accumulation of alveolar (mostly CD68+) and interstitial (CD68+ and CD163+) lung macrophages. Analysis of cytokine profiles in lung tissue lysates showed a hypoxia-induced upregulation of TIMP-1, CINC-1, and Fractalkine and downregulation of soluble ICAM (sICAM). The expression of Fractalkine and VEGFα, but not CINC-1, TIMP-1, and sICAM was downregulated by butyrate. In rat microvascular endothelial cells (RMVEC), butyrate (1 mM, 2 and 24 h) exhibited a protective effect against TNFα- and LPS-induced barrier disruption. Butyrate (1 mM, 24 h) also upregulated tight junctional proteins (occludin, cingulin, claudin-1) and increased the acetylation of histone H3 but not α-tubulin. These findings provide evidence of the protective effect of butyrate on hypoxic PH and suggest its potential use as a complementary treatment for PH and other cardiovascular diseases.

scholarly journals Notch4 mediates vascular remodeling via ERK/JNK/P38 MAPK signaling pathways in hypoxic pulmonary hypertension

2022 ◽  
Vol 23 (1) ◽  
Author(s):  
Mingzhou Guo ◽  
Mengzhe Zhang ◽  
Xiaopei Cao ◽  
Xiaoyu Fang ◽  
Ke Li ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Signaling Pathways ◽  
P38 Mapk ◽  
Vascular Remodeling ◽  
Cell Surface Receptor ◽  
Cell Counting ◽  
Pulmonary Vascular Remodeling ◽  
Hypoxic Pulmonary Hypertension ◽  
And Migration

Abstract Background Hypoxic pulmonary hypertension (HPH) is a chronic progressive advanced disorder pathologically characterized by pulmonary vascular remodeling. Notch4 as a cell surface receptor is critical for vascular development. However, little is known about the role and mechanism of Notch4 in the development of hypoxic vascular remodeling. Methods Lung tissue samples were collected to detect the expression of Notch4 from patients with HPH and matched controls. Human pulmonary artery smooth muscle cells (HPASMCs) were cultured in hypoxic and normoxic conditions. Real-time quantitative PCR and western blotting were used to examine the mRNA and protein levels of Notch4. HPASMCs were transfected with small interference RNA (siRNA) against Notch4 or Notch4 overexpression plasmid, respectively. Cell viability, cell proliferation, apoptosis, and migration were assessed using Cell Counting Kit-8, Edu, Annexin-V/PI, and Transwell assay. The interaction between Notch4 and ERK, JNK, P38 MAPK were analyzed by co-immunoprecipitation. Adeno-associated virus 1-mediated siRNA against Notch4 (AAV1-si-Notch4) was injected into the airways of hypoxic rats. Right ventricular systolic pressure (RVSP), right ventricular hypertrophy and pulmonary vascular remodeling were evaluated. Results In this study, we demonstrate that Notch4 is highly expressed in the media of pulmonary vascular and is upregulated in lung tissues from patients with HPH and HPH rats compared with control groups. In vitro, hypoxia induces the high expression of Delta-4 and Notch4 in HPASMCs. The increased expression of Notch4 promotes HPASMCs proliferation and migration and inhibits cells apoptosis via ERK, JNK, P38 signaling pathways. Furthermore, co-immunoprecipitation result elucidates the interaction between Notch4 and ERK/JNK/P38. In vivo, silencing Notch4 partly abolished the increase in RVSP and pulmonary vascular remodeling caused by hypoxia in HPH rats. Conclusions These findings reveal an important role of the Notch4-ERK/JNK/P38 MAPK axis in hypoxic pulmonary remodeling and provide a potential therapeutic target for patients with HPH.

α1-Adrenoceptor-dependent vascular hypertrophy and remodeling in murine hypoxic pulmonary hypertension

2007 ◽  
Vol 292 (5) ◽  
pp. H2316-H2323 ◽  
Author(s):  
James E. Faber ◽  
Caroline L. Szymeczek ◽  
Susanna Cotecchia ◽  
Steven A. Thomas ◽  
Akito Tanoue ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Pulmonary Arteries ◽  
Vascular Wall ◽  
Ventricular Pressure ◽  
Hypoxic Pulmonary Hypertension ◽  
Oxygen Fraction ◽  
Stimulation Of

Excessive proliferation of vascular wall cells underlies the development of elevated vascular resistance in hypoxic pulmonary hypertension (PH), but the responsible mechanisms remain unclear. Growth-promoting effects of catecholamines may contribute. Hypoxemia causes sympathoexcitation, and prolonged stimulation of α1-adrenoceptors (α1-ARs) induces hypertrophy and hyperplasia of arterial smooth muscle cells and adventitial fibroblasts. Catecholamine trophic actions in arteries are enhanced when other conditions favoring growth or remodeling are present, e.g., injury or altered shear stress, in isolated pulmonary arteries from rats with hypoxic PH. The present study examined the hypothesis that catecholamines contribute to pulmonary vascular remodeling in vivo in hypoxic PH. Mice genetically deficient in norepinephrine and epinephrine production [dopamine β-hydroxylase−/− (DBH−/−)] or α1-ARs were examined for alterations in PH, cardiac hypertrophy, and vascular remodeling after 21 days exposure to normobaric 0.1 inspired oxygen fraction (FiO2). A decrease in the lumen area and an increase in the wall thickness of arteries were strongly inhibited in knockout mice (order of extent of inhibition: DBH−/− = α1D-AR−/− > α1B-AR−/−). Distal muscularization of small arterioles was also reduced (DBH−/− > α1D-AR−/− > α1B-AR−/− mice). Despite these reductions, increases in right ventricular pressure and hypertrophy were not attenuated in DBH−/− and α1B-AR−/− mice. However, hematocrit increased more in these mice, possibly as a consequence of impaired cardiovascular activation that occurs during reduction of FiO2. In contrast, in α1D-AR−/− mice, where hematocrit increased the same as in wild-type mice, right ventricular pressure was reduced. These data suggest that catecholamine stimulation of α1B- and α1D-ARs contributes significantly to vascular remodeling in hypoxic PH.

ETA-receptor antagonist prevents and reverses chronic hypoxia-induced pulmonary hypertension in rat

1995 ◽  
Vol 269 (5) ◽  
pp. L690-L697 ◽  
Author(s):  
V. S. DiCarlo ◽  
S. J. Chen ◽  
Q. C. Meng ◽  
J. Durand ◽  
M. Yano ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Receptor Antagonist ◽  
Vascular Remodeling ◽  
Ventricular Hypertrophy ◽  
Chronic Hypoxia ◽  
Right Ventricular Hypertrophy ◽  
Pulmonary Vascular Remodeling ◽  
Eta Receptor ◽  
Eta Receptor Antagonist

The selective endothelin-A (ETA)-receptor antagonist BQ-123 has been shown to prevent chronic hypoxia-induced pulmonary hypertension in the rat. Therefore in the current study we utilized BQ-123 to test the hypothesis that blockade of the ETA receptor can reverse as well as prevent the increase in mean pulmonary artery pressure, right ventricle-to-left ventricle plus septum ratio, and percent wall thickness in small (50-100 microns) pulmonary arteries observed in male Sprague-Dawley rats exposed to normobaric hypoxia (10% O2, 2 wk). Infusion of BQ-123 (0.4 mg.0.5 microliter-1.h-1 for 2 wk in 10% O2) begun after 2 wk of hypoxia significantly reversed the established pulmonary hypertension and prevented further progression of right ventricular hypertrophy during the third and fourth week of hypoxia. BQ-123 infusion instituted before exposure to hypoxia completely prevented the hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular remodeling. These findings suggest that, in the lung, hypoxia induced an increase synthesis of endothelin-1, which acts locally on ETA receptors to cause pulmonary hypertension, right heart hypertrophy, and pulmonary vascular remodeling, while ETA-receptor blockade can both prevent and reverse these processes.

scholarly journals Stim-activated TRPC-ORAI channels in pulmonary hypertension induced by chronic intermittent hypoxia

2020 ◽  
Vol 10 (1_suppl) ◽  
pp. 13-22
Author(s):  
Sebastian Castillo-Galán ◽  
German A. Arenas ◽  
Roberto V. Reyes ◽  
Bernardo J. Krause ◽  
Rodrigo Iturriaga
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Intermittent Hypoxia ◽  
Systolic Pressure ◽  
Transient Receptor Potential Channels ◽  
Chronic Intermittent Hypoxia ◽  
Ventricular Ejection Fraction ◽  
Pulmonary Vascular Remodeling ◽  
Obstructive Sleep

Obstructive sleep apnea (OSA), a breathing disorder featured by chronic intermittent hypoxia (CIH) is associated with pulmonary hypertension (PH). Rodents exposed to CIH develop pulmonary vascular remodeling and PH, but the pathogenic mechanisms are not well known. Overexpression of Stim-activated Transient Receptor Potential Channels (TRPC) and Calcium Release-Activated Calcium Channel Protein (ORAI) TRPC-ORAI Ca2+ channels (STOC) has been involved in pulmonary vascular remodeling and PH in sustained hypoxia. However, it is not known if CIH may change STOC levels. Accordingly, we studied the effects of CIH on the expression of STOC subunits in the lung and if these changes paralleled the progression of the vascular pulmonary remodeling and PH in a preclinical model of OSA. Male Sprague-Dawley rats (∼200 g) were exposed to CIH (5%O2, 12 times/h for 8 h) for 14, 21, and 28 days. We measured right ventricular systolic pressure (RVSP), cardiac morphometry with MRI, pulmonary vascular remodeling, and wire-myographic arterial responses to KCl and endothelin-1 (ET-1). Pulmonary RNA and protein STOC levels of TRPC1, TRPC4, TRPC6, ORAI 1, ORAI 2, and STIM1 subunits were measured by qPCR and western blot, and results were compared with age-matched controls. CIH elicited a progressive increase of RVSP and vascular contractile responses to KCl and ET-1, leading to vascular remodeling and augmented right ventricular ejection fraction, which was significant at 28 days of CIH. The levels of TRPC1, TRPC4, TRPC 6, ORAI 1, and STIM 1 channels increased following CIH, and some of them paralleled morphologic and functional changes. Our findings show that CIH increased pulmonary STOC expression, paralleling vascular remodeling and PH.

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