scholarly journals Mineralocorticoid receptor antagonism attenuates experimental pulmonary hypertension

2013 ◽  
Vol 304 (10) ◽  
pp. L678-L688 ◽  
Author(s):  
Ioana R. Preston ◽  
Kristen D. Sagliani ◽  
Rod R. Warburton ◽  
Nicholas S. Hill ◽  
Barry L. Fanburg ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Vascular Remodeling ◽  
Mineralocorticoid Receptor ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Pulmonary Vascular Remodeling

Mineralocorticoid receptor (MR) activation stimulates systemic vascular and left ventricular remodeling. We hypothesized that MR contributes to pulmonary vascular and right ventricular (RV) remodeling of pulmonary hypertension (PH). We evaluated the efficacy of MR antagonism by spironolactone in two experimental PH models; mouse chronic hypoxia-induced PH (prevention model) and rat monocrotaline-induced PH (prevention and treatment models). Last, the biological function of the MR was analyzed in cultured distal pulmonary artery smooth muscle cells (PASMCs). In hypoxic PH mice, spironolactone attenuated the increase in RV systolic pressure, pulmonary arterial muscularization, and RV fibrosis. In rat monocrotaline-induced PH (prevention arm), spironolactone attenuated pulmonary vascular resistance and pulmonary vascular remodeling. In the established disease (treatment arm), spironolactone decreased RV systolic pressure and pulmonary vascular resistance with no significant effect on histological measures of pulmonary vascular remodeling, or RV fibrosis. Spironolactone decreased RV cardiomyocyte size modestly with no significant effect on RV mass, systemic blood pressure, cardiac output, or body weight, suggesting a predominantly local pulmonary vascular effect. In distal PASMCs, MR was expressed and localized diffusely. Treatment with the MR agonist aldosterone, hypoxia, or platelet-derived growth factor promoted MR translocation to the nucleus, activated MR transcriptional function, and stimulated PASMC proliferation, while spironolactone blocked these effects. In summary, MR is active in distal PASMCs, and its antagonism prevents PASMC proliferation and attenuates experimental PH. These data suggest that MR is involved in the pathogenesis of PH via effects on PASMCs and that MR antagonism may represent a novel therapeutic target for this disease.

scholarly journals Chronic Inhibition of Toll‐Like Receptor 9 Ameliorates Pulmonary Hypertension in Rats

2021 ◽  
Vol 10 (7) ◽  
Author(s):  
Tomohito Ishikawa ◽  
Kohtaro Abe ◽  
Mariko Takana‐Ishikawa ◽  
Keimei Yoshida ◽  
Takanori Watanabe ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Interleukin 6 ◽  
Vascular Remodeling ◽  
Mrna Level ◽  
Systolic Pressure ◽  
Resistance Index ◽  
Pulmonary Vascular Resistance Index ◽  
Macrophage Accumulation

Background Recent accumulating evidence suggests that toll‐like receptor 9 (TLR9) is involved in the pathogenesis of cardiovascular diseases. However, its role in pulmonary hypertension remains uncertain. We hypothesized that TLR9 is involved in the development of pulmonary hypertension. Methods and Results A rat model of monocrotaline‐induced pulmonary hypertension was used to investigate the effects of TLR9 on hemodynamic parameters, vascular remodeling, and survival. Monocrotaline‐exposed rats significantly showed increases in plasma levels of mitochondrial DNA markers, which are recognized by TLR9, TLR9 activation in the lung, and interleukin‐6 mRNA level in the lung on day 14 after monocrotaline injection. Meanwhile, monocrotaline‐exposed rats showed elevated right ventricular systolic pressure, total pulmonary vascular resistance index and vascular remodeling, together with macrophage accumulation on day 21. In the preventive protocol, administration (days −3 to 21 after monocrotaline injection) of selective (E6446) or nonselective TLR9 inhibitor (chloroquine) significantly ameliorated the elevations of right ventricular systolic pressure and total pulmonary vascular resistance index as well as vascular remodeling and macrophage accumulation on day 21. These inhibitors also significantly reduced NF‐κB activation and interleukin‐6 mRNA levels to a similar extent. In the short‐term reversal protocol, E646 treatment (days 14–17 after monocrotaline injection) almost normalized NF‐κB activation and interleukin‐6 mRNA level, and reduced macrophage accumulation. In the prolonged reversal protocol, E6446 treatment (days 14–24 after monocrotaline injection) reversed total pulmonary vascular resistance index and vascular remodeling, and improved survival in monocrotaline‐exposed rats. Conclusions TLR9 is involved in the development of pulmonary hypertension concomitant via activation of the NF‐κB‒IL‐6 pathway. Inhibition of TLR9 may be a novel therapeutic strategy for pulmonary hypertension.

scholarly journals HIF2α–arginase axis is essential for the development of pulmonary hypertension

2016 ◽  
Vol 113 (31) ◽  
pp. 8801-8806 ◽  
Author(s):  
Andrew S. Cowburn ◽  
Alexi Crosby ◽  
David Macias ◽  
Cristina Branco ◽  
Renato D. D. R. Colaço ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Systolic Pressure ◽  
Hypoxic Exposure ◽  
Pulmonary Vascular Remodeling ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Endothelium ◽  
Arginase 1

Hypoxic pulmonary vasoconstriction is correlated with pulmonary vascular remodeling. The hypoxia-inducible transcription factors (HIFs) HIF-1α and HIF-2α are known to contribute to the process of hypoxic pulmonary vascular remodeling; however, the specific role of pulmonary endothelial HIF expression in this process, and in the physiological process of vasoconstriction in response to hypoxia, remains unclear. Here we show that pulmonary endothelial HIF-2α is a critical regulator of hypoxia-induced pulmonary arterial hypertension. The rise in right ventricular systolic pressure (RVSP) normally observed following chronic hypoxic exposure was absent in mice with pulmonary endothelial HIF-2α deletion. The RVSP of mice lacking HIF-2α in pulmonary endothelium after exposure to hypoxia was not significantly different from normoxic WT mice and much lower than the RVSP values seen in WT littermate controls and mice with pulmonary endothelial deletion of HIF-1α exposed to hypoxia. Endothelial HIF-2α deletion also protected mice from hypoxia remodeling. Pulmonary endothelial deletion of arginase-1, a downstream target of HIF-2α, likewise attenuated many of the pathophysiological symptoms associated with hypoxic pulmonary hypertension. We propose a mechanism whereby chronic hypoxia enhances HIF-2α stability, which causes increased arginase expression and dysregulates normal vascular NO homeostasis. These data offer new insight into the role of pulmonary endothelial HIF-2α in regulating the pulmonary vascular response to hypoxia.

scholarly journals Cellular Pathways Promoting Pulmonary Vascular Remodeling by Hypoxia

Physiology ◽  
2020 ◽  
Vol 35 (4) ◽  
pp. 222-233
Author(s):  
Larissa A. Shimoda
Keyword(s):  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Vascular Remodeling ◽  
Pulmonary Arterial Pressure ◽  
Right Heart Failure ◽  
Right Heart ◽  
Pulmonary Vascular Remodeling ◽  
Vascular Stiffening ◽  
Pulmonary Arterial ◽  
Cellular Pathways

Exposure to hypoxia increases pulmonary vascular resistance, leading to elevated pulmonary arterial pressure and, potentially, right heart failure. Vascular remodeling is an important contributor to the increased pulmonary vascular resistance. Hyperproliferation of smooth muscle, endothelial cells, and fibroblasts, and deposition of extracellular matrix lead to increased wall thickness, extension of muscle into normally non-muscular arterioles, and vascular stiffening. This review highlights intrinsic and extrinsic modulators contributing to the remodeling process.

Abstract P300: Cardiac Ly6C high Monocyte Accumulation and Remodeling Depend on the Mineralocorticoid Receptor in Endothelial Cells

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Achim Lother ◽  
Aurelia Hübner ◽  
Ingo Hilgendorf ◽  
Tilman Schnick ◽  
Martin Moser ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Diastolic Dysfunction ◽  
Mineralocorticoid Receptor ◽  
Cardiac Fibrosis ◽  
Ventricular Remodeling ◽  
Interstitial Fibrosis ◽  
Left Ventricular Remodeling ◽  
Marker Gene ◽  
Pressure Overload ◽  
Left Ventricular

Introduction: Inflammation is a key driver for the development of cardiac fibrosis and diastolic dysfunction. Aldosterone promotes the expression of adhesion molecules and vascular inflammation. Thus, the goal of the present study was to examine the significance of endothelial MR for pressure overload induced cardiac inflammation and remodeling. Methods and results: Mice with endothelial cell-specific deletion of the mineralocorticoid receptor (MR Cdh5Cre ) were generated using the Cre/loxP system. MR Cdh5Cre and Cre-negative littermates (MR wildtype ) underwent transverse aortic constriction (TAC, n=5-7 per group). After two weeks of pressure overload echocardiography revealed diastolic dysfunction in MR wildtype (mitral valve E acceleration time TAC 15.7 ± 0.5 vs. sham 12.8 ± 0.4 ms, P<0.05) but not in MR Cdh5Cre mice (TAC 11.2 ± 0.6 vs. sham 12.2 ± 0.9 ms, n.s.). Cardiac hypertrophy (ventricle weight 143.2 ± 5.2 vs. MR wildtype 167.3 ± 6.7 mg, P<0.001) and interstitial fibrosis (sirius red stained area 8.2 ± 4.7 vs. MR wildtype 13.5 ± 4.5 %, P<0.05) following TAC were attenuated in MR Cdh5Cre mice. mRNA expression of atrial natriuretic peptide ( Nppa , 2429 ± 1230 vs. MR wildtype 7051 ± 3182 copies/10 4 copies Rps29 , P<0.01) or the fibrosis marker gene collagen 1a1 ( Col1a1 , 256 ± 89 vs. MR wildtype 432 ± 165 copies/10 4 copies Rps29 , P<0.05) as determined by qRT-PCR confirmed these findings. Cardiac leukocytes were quantitatively analyzed by fluorescence assisted cell sorting using specific antibodies. Numbers of CD45 + leukocytes were similarly increased after TAC in the hearts of both genotypes (MR Cdh5Cre 3840 ± 443 vs. MR wildtype 4051 ± 385 /mg tissue, n.s.). Subtype analysis revealed a shift towards CD45 + CD11b + F4/80 low Ly6C high monocytes vs. CD45 + CD11b + F4/80 high Ly6C low macrophages in the heart of MR wildtype (TAC 20 ± 6 vs. sham 4 ± 1 % of CD45 + CD11b + , P<0.05) but not of MR Cdh5Cre mice (TAC 6 ± 2 vs. sham 3 ± 1 % of CD45 + CD11b + , n.s.). Conclusion: MR deletion from endothelial cells ameliorates left ventricular remodeling and diastolic dysfunction after pressure overload. The protective effect of endothelial MR deletion is associated with a shift towards less pro-inflammatory Ly6C high monocytes and more reparative Ly6C low macrophages.

scholarly journals Purinergic Dysfunction in Pulmonary Arterial Hypertension

2020 ◽  
Vol 9 (18) ◽  
Author(s):  
Zongye Cai ◽  
Ly Tu ◽  
Christophe Guignabert ◽  
Daphne Merkus ◽  
Zhichao Zhou
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Right Ventricle ◽  
Arterial Hypertension ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Vascular Remodeling ◽  
Purinergic Signaling ◽  
Receptor Activation ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial

Abstract Pulmonary arterial hypertension (PAH) is a life‐threatening disease characterized by increased pulmonary arterial pressure and pulmonary vascular resistance, which result in an increase in afterload imposed onto the right ventricle, leading to right heart failure. Current therapies are incapable of reversing the disease progression. Thus, the identification of novel and potential therapeutic targets is urgently needed. An alteration of nucleotide‐ and nucleoside‐activated purinergic signaling has been proposed as a potential contributor in the pathogenesis of PAH. Adenosine‐mediated purinergic 1 receptor activation, particularly A 2A R activation, reduces pulmonary vascular resistance and attenuates pulmonary vascular remodeling and right ventricle hypertrophy, thereby exerting a protective effect. Conversely, A 2B R activation induces pulmonary vascular remodeling, and is therefore deleterious. ATP‐mediated P2X 7 R activation and ADP‐mediated activation of P2Y 1 R and P2Y 12 R play a role in pulmonary vascular tone, vascular remodeling, and inflammation in PAH. Recent studies have revealed a role of ectonucleotidase nucleoside triphosphate diphosphohydrolase, that degrades ATP/ADP, in regulation of pulmonary vascular remodeling. Interestingly, existing evidence that adenosine activates erythrocyte A 2B R signaling, counteracting hypoxia‐induced pulmonary injury, and that ATP release is impaired in erythrocyte in PAH implies erythrocyte dysfunction as an important trigger to affect purinergic signaling for pathogenesis of PAH. The present review focuses on current knowledge on alteration of nucleot(s)ide‐mediated purinergic signaling as a potential disease mechanism underlying the development of PAH.

Inhaled nitric oxide improves hemodynamics in patients with acute pulmonary hypertension after high-risk cardiac surgery

Perfusion ◽  
1999 ◽  
Vol 14 (1) ◽  
pp. 37-42 ◽  
Author(s):  
J R Beck ◽  
L B Mongero ◽  
R M Kroslowitz ◽  
A F Choudhri ◽  
J M Chen ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Cardiac Surgery ◽  
High Risk ◽  
Right Ventricular ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Left Ventricular ◽  
Ventricular Assist ◽  
Acute Pulmonary Hypertension

Severe pulmonary hypertension and right-sided circulatory failure (RSCF) represent an increasing cause of morbidity and mortality in patients undergoing high-risk cardiac surgery. Increased pulmonary vascular resistance in the setting of cardiopulmonary bypass (CPB) may further lead to decreased blood flow across the pulmonary vascular bed; thereby decreasing left ventricular filling and cardiac output. Current management techniques for RSCF include both nonspecific vasodilator and inotropic agents (often limited by systemic hypotension) and the placement of right ventricular assist devices (associated with increased perioperative morbidity). Inhaled nitric oxide (NOi) represents a novel, specific pulmonary vasodilator that has been proven efficacious in these clinical settings. We evaluated 34 patients in 38 operations who underwent cardiac surgery at Columbia Presbyterian Medical Center, and who received NOi (20 ppm) through a modified ventilatory circuit for hemodynamically significant elevations in pulmonary vascular resistance. Nine patients underwent cardiac transplantation, three patients bilateral lung transplantation, 16 patients left ventricular assist device placement and 10 patients routine cardiac surgery. Patients receiving NOi exhibited substantial reductions in mean pulmonary artery pressure (mPAP) (34.6 ± 2.0 to 26.0 ± 1.7 mmHg, p < 0.0001), with improvements in systemic hemodynamics, mean arterial pressure (68 ± 3.1 to 75.9 ± 2.0 mmHg, p = 0.006). In five cases, patients could not be weaned from CPB until NOi was administered. Patients were maintained on NOi from 6 to 240 h postoperatively (median duration 36 h). Inhaled NO induces substantial reductions in mPAP and increases in both cardiac index and systemic blood pressure in patients displaying elevated pulmonary hemodynamics after high-risk cardiac surgery. NO is, therefore, a useful adjunct in these patients in whom acute pulmonary hypertension threatens right ventricular function and hemodynamic stability.

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.

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