scholarly journals Pulmonary Hypertension Remodels the Genomic Fabrics of Major Functional Pathways

2019 ◽  
Author(s):  
Rajamma Mathew ◽  
Jing Huang ◽  
Sanda Iacobas ◽  
Dumitru Iacobas
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Aerobic Glycolysis ◽  
Systolic Pressure ◽  
Smooth Muscle Contraction ◽  
Male Rats ◽  
Wall Thickening ◽  
High Morbidity ◽  
Antioxidant Genes ◽  
Ventricular Systolic Pressure

Pulmonary hypertension (PH) is a serious disorder with high morbidity and mortality rate. We analyzed the right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH), lung histology and transcriptomes of six weeks old male rats with PH induced by: 1) hypoxia (HO), 2) administration of monocrotaline (CM) or 3) administration of monocrotaline and exposure to hypoxia (HM). The results in PH rats were compared to those in control rats (CO). After four weeks exposure, increased RVSP and RVH, pulmonary arterial wall thickening, and alteration of the lung transcriptome were observed in all PH groups. The HM group exhibited the largest alterations and also neointimal lesions and obliteration of lumen in small arteries. We found that the PH increased the expression of caveolin1, matrix metallopeptidase 2 and numerous inflammatory and cell proliferation genes. The cell-cycle, vascular smooth muscle contraction and the oxidative phosphorylation pathways, as well as their interplay were largely perturbed. Our results also suggest that the up-regulated Rhoa (ras homolog family member A) mediates its action through expression coordination with several ATPases. The upregulation of antioxidant genes and the extensive mitochondrial damage observed especially in HM group, indicate metabolic shift towards aerobic glycolysis.

scholarly journals Pulmonary Hypertension Remodels the Genomic Fabrics of Major Functional Pathways

Genes ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 126 ◽  
Author(s):  
Rajamma Mathew ◽  
Jing Huang ◽  
Sanda Iacobas ◽  
Dumitru A. Iacobas
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Aerobic Glycolysis ◽  
Systolic Pressure ◽  
Smooth Muscle Contraction ◽  
Male Rats ◽  
Wall Thickening ◽  
High Morbidity ◽  
Antioxidant Genes ◽  
Ventricular Systolic Pressure

Pulmonary hypertension (PH) is a serious disorder with high morbidity and mortality rate. We analyzed the right-ventricular systolic pressure (RVSP), right-ventricular hypertrophy (RVH), lung histology, and transcriptomes of six-week-old male rats with PH induced by (1) hypoxia (HO), (2) administration of monocrotaline (CM), or (3) administration of monocrotaline and exposure to hypoxia (HM). The results in PH rats were compared to those in control rats (CO). After four weeks exposure, increased RVSP and RVH, pulmonary arterial wall thickening, and alteration of the lung transcriptome were observed in all PH groups. The HM group exhibited the largest alterations, as well as neointimal lesions and obliteration of the lumen in small arteries. We found that PH increased the expression of caveolin1, matrix metallopeptidase 2, and numerous inflammatory and cell proliferation genes. The cell cycle, vascular smooth muscle contraction, and oxidative phosphorylation pathways, as well as their interplay, were largely perturbed. Our results also suggest that the upregulated Rhoa (Ras homolog family member A) mediates its action through expression coordination with several ATPases. The upregulation of antioxidant genes and the extensive mitochondrial damage observed, especially in the HM group, indicate metabolic shift toward aerobic glycolysis.

scholarly journals JNK2 regulates vascular remodeling in pulmonary hypertension

2018 ◽  
Vol 8 (3) ◽  
pp. 204589401877815
Author(s):  
Mita Das ◽  
W. Michael Zawada ◽  
James West ◽  
Kurt R. Stenmark
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Wall Thickening ◽  
Ventricular Systolic Pressure ◽  
Vascular Abnormalities ◽  
Map Kinase Phosphatase ◽  
Pulmonary Arterial ◽  
Jnk Isoforms

Pulmonary arterial (PA) wall modifications are key pathological features of pulmonary hypertension (PH). Although such abnormalities correlate with heightened phosphorylation of c-Jun N-terminal kinases 1/2 (JNK1/2) in a rat model of PH, the contribution of specific JNK isoforms to the pathophysiology of PH is unknown. Hence, we hypothesized that activation of either one, or both JNK isoforms regulates PA remodeling in PH. We detected increased JNK1/2 phosphorylation in the thickened vessels of PH patients’ lungs compared to that in lungs of healthy individuals. JNK1/2 phosphorylation paralleled a marked reduction in MAP kinase phosphatase 1 (JNK dephosphorylator) expression in patients’ lungs. Association of JNK1/2 activation with vascular modification was confirmed in the calf model of severe hypoxia-induced PH. To ascertain the role of each JNK isoform in pathophysiology of PH, wild-type (WT), JNK1 null (JNK1-/-), and JNK2 null (JNK2-/-) mice were exposed to chronic hypoxia (10% O2 for six weeks) to develop PH. In hypoxic WT lungs, an increase in JNK1/2 phosphorylation was associated with PH-like pathology. Hallmarks of PH pathophysiology, i.e. excessive accumulation of extracellular matrix and vessel muscularization with medial wall thickening, was also detected in hypoxic JNK1-/- lungs, but not in hypoxia-exposed JNK2-/- lungs. However, hypoxia-induced increases in right ventricular systolic pressure (RVSP) and in right ventricular hypertrophy (RVH) were similar in all three genotypes. Our findings suggest that JNK2 participates in PA remodeling (but likely not in vasoconstriction) in murine hypoxic PH and that modulating JNK2 actions might quell vascular abnormalities and limit the course of PH.

scholarly journals Magnesium Sulfate Mitigates the Progression of Monocrotaline Pulmonary Hypertension in Rats

2019 ◽  
Vol 20 (18) ◽  
pp. 4622 ◽  
Author(s):  
Chao-Yuan Chang ◽  
Hung-Jen Shih ◽  
I-Tao Huang ◽  
Pei-Shan Tsai ◽  
Kung-Yen Chen ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Right Ventricular ◽  
Magnesium Sulfate ◽  
Ventricular Hypertrophy ◽  
Systolic Pressure ◽  
Right Ventricular Hypertrophy ◽  
Male Rats ◽  
Wall Thickening ◽  
Artery Wall

We investigated whether magnesium sulfate (MgSO4) mitigated pulmonary hypertension progression in rats. Pulmonary hypertension was induced by a single intraperitoneal injection of monocrotaline (60 mg/kg). MgSO4 (100 mg/kg) was intraperitoneally administered daily for 3 weeks, from the seventh day after monocrotaline injection. Adult male rats were randomized into monocrotaline (MCT) or monocrotaline plus MgSO4 (MM) groups (n = 15 per group); control groups were maintained simultaneously. For analysis, surviving rats were euthanized on the 28th day after receiving monocrotaline. The survival rate was higher in the MM group than in the MCT group (100% versus 73.3%, p = 0.043). Levels of pulmonary artery wall thickening, α-smooth muscle actin upregulation, right ventricular systolic pressure increase, and right ventricular hypertrophy were lower in the MM group than in the MCT group (all p < 0.05). Levels of lipid peroxidation, mitochondrial injury, inflammasomes and cytokine upregulation, and apoptosis in the lungs and right ventricle were lower in the MM group than in the MCT group (all p < 0.05). Notably, the mitigation effects of MgSO4 on pulmonary artery wall thickening and right ventricular hypertrophy were counteracted by exogenous calcium chloride. In conclusion, MgSO4 mitigates pulmonary hypertension progression, possibly by antagonizing calcium.

Abstract P272: Involvement of Neuro-Inflammation in the Pathogenesis of MCT-Induced Pulmonary Hypertension

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Ravindra K Sharma ◽  
Vinayak Shenoy ◽  
Ashok Kumar ◽  
Avinash Mandloi ◽  
Michael J Katovich ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Microglial Activation ◽  
Systolic Pressure ◽  
Fold Increase ◽  
Brain Regions ◽  
Microglial Cells ◽  
Male Rats ◽  
Ventricular Systolic Pressure ◽  
Neuro Inflammation

Background: Pulmonary hypertension (PH) is a devastating disease characterized by increase in pulmonary pressure that eventually leads to right heart failure and death. PH is associated with heightened circulatory cytokines and infiltration of inflammatory cells within the diseased lungs. However, involvement of inflammation within the central nervous system (CNS) in PH pathophysiology has never been investigated. Emerging evidence suggest that activated microglial cells and neuro-inflammation within the CNS play an important role in the pathology of several CNS disorders, including resistant hypertension. Objective: These observations led us to propose the hypothesis that microglial activation and neuro-inflammation in the autonomic brain regions play regulatory role in PH. Minocycline (Mino), an anti-inflammatory antibiotic, which has been reported to inhibit microglial activation in the autonomic brain regions, was used to test this hypothesis. Methods: PH was induced in adult male rats by a single injection of monocrotaline (MCT; 50mg/kg sc). A subset of MCT-injected animals was infused intracerebroventricularly (ICV) with Mino (20mg/ml). After 4 weeks of treatment, animals were sacrificed for the measurement of physiological and pathological parameters. Results: ICV infusion of Mino significantly attenuated right ventricular systolic pressure (RVSP; Con: 30.1±5, MCT: 76.1±14, MCT+Mino: 50.1±11 mmHg) and right ventricular hypertrophy (RVH; Con: 0.26±0.02, MCT: 0.49±0.12, MCT+Mino: 0.38+0.1) induced by MCT. MCT administration resulted in ~2 fold increase in microglial cells, predominantly in the hypothalamic paraventricular nucleus (PVN), an effect significantly attenuated by ICV Mino (Con: 4.0±1.0, MCT: 8.6±1.1, MCT+Mino: 5.0±1.0). MCT injection increased pro-inflammatory cytokines [IL-1β (155%), TNF-α (165%) and IL-6 (113%)] and decreased IL-10 (46%) levels in the PVN. However, ICV Mino treatment restored these cytokines to control levels. Conclusion: Our observations demonstrate that microglial activation in the PVN is involved in PH pathophysiology. They, for the first time, suggest the involvement of neuro-inflammation and autonomic dysregulation in the development and establishment of PH.

Serotonin transporter is not required for the development of severe pulmonary hypertension in the Sugen hypoxia rat model

2015 ◽  
Vol 309 (10) ◽  
pp. L1164-L1173 ◽  
Author(s):  
Michiel Alexander de Raaf ◽  
Yvet Kroeze ◽  
Anthonieke Middelman ◽  
Frances S. de Man ◽  
Helma de Jong ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Serotonin Transporter ◽  
Rat Model ◽  
Systolic Pressure ◽  
Serum Levels ◽  
Normal Function ◽  
Ventricular Systolic Pressure ◽  
Serotonin System ◽  
Pulmonary Arterial

Increased serotonin serum levels have been proposed to play a key role in pulmonary arterial hypertension (PAH) by regulating vessel tone and vascular smooth muscle cell proliferation. An intact serotonin system, which critically depends on a normal function of the serotonin transporter (SERT), is required for the development of experimental pulmonary hypertension in rodents exposed to hypoxia or monocrotaline. While these animal models resemble human PAH only with respect to vascular media remodeling, we hypothesized that SERT is likewise required for the presence of lumen-obliterating intima remodeling, a hallmark of human PAH reproduced in the Sugen hypoxia (SuHx) rat model of severe angioproliferative pulmonary hypertension. Therefore, SERT wild-type (WT) and knockout (KO) rats were exposed to the SuHx protocol. SERT KO rats, while completely lacking SERT, were hemodynamically indistinguishable from WT rats. After exposure to SuHx, similar degrees of severe angioproliferative pulmonary hypertension and right ventricular hypertrophy developed in WT and KO rats (right ventricular systolic pressure 60 vs. 55 mmHg, intima thickness 38 vs. 30%, respectively). In conclusion, despite its implicated importance in PAH, SERT does not play an essential role in the pathogenesis of severe angioobliterative pulmonary hypertension in rats exposed to SuHx.

Anti-monocyte chemoattractant protein-1 gene therapy attenuates pulmonary hypertension in rats

2002 ◽  
Vol 283 (5) ◽  
pp. H2021-H2028 ◽  
Author(s):  
Yasuhiro Ikeda ◽  
Yoshikazu Yonemitsu ◽  
Chu Kataoka ◽  
Shiro Kitamoto ◽  
Terutoshi Yamaoka ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Mononuclear Cells ◽  
Systolic Pressure ◽  
Signal Pathway ◽  
Dominant Negative ◽  
Monocyte Chemoattractant Protein 1 ◽  
Ventricular Systolic Pressure

Monocyte/macrophage chemoattractant protein-1 (MCP-1), a potent chemoattractant chemokine and an activator for mononuclear cells, may play a role in the initiation and/or progression of pulmonary hypertension (PH). To determine whether blockade of a systemic MCP-1 signal pathway in vivo may prevent PH, we intramuscularly transduced a naked plasmid encoding a 7-NH2terminus-deleted dominant negative inhibitor of the MCP-1 (7ND MCP-1) gene in monocrotaline-induced PH. We also simultaneously gave a duplicate transfection at 2-wk intervals or skeletal muscle-directed in vivo electroporation (EP) to evaluate whether a longer or higher expression might be more effective. The intramuscular reporter gene expression was enhanced 10 times over that by EP than by simple injection, and a significant 7ND MCP-1 protein in plasma was detected only in the EP group. 7ND MCP-1 gene transfer significantly inhibited the progression of MCT-induced PH as evaluated by right ventricular systolic pressure, right ventricular hypertrophy, medial hypertrophy of pulumonary arterioles, and mononuclear cell infiltration into the lung. Differential effects of longer or higher transgene expression were not apparent. Although the in vivo kinetics of 7ND MCP-1 gene therapy should be studied further, these encouraging results suggest that an anti-inflammatory strategy via blockade of the MCP-1 signal pathway may be an alternative approach to treat subjects with PH.

scholarly journals Chronic Hypoxia Decreases Endothelial Connexin 40, Attenuates Endothelium‐Dependent Hyperpolarization–Mediated Relaxation in Small Distal Pulmonary Arteries, and Leads to Pulmonary Hypertension

2020 ◽  
Vol 9 (24) ◽  
Author(s):  
Rui Si ◽  
Qian Zhang ◽  
Jody Tori O. Cabrera ◽  
Qiuyu Zheng ◽  
Atsumi Tsuji‐Hosokawa ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Knockout Mice ◽  
Chronic Hypoxia ◽  
Systolic Pressure ◽  
Right Ventricular Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Endothelial Cells ◽  
Endothelium Dependent Relaxation

Background Abnormal endothelial function in the lungs is implicated in the development of pulmonary hypertension; however, there is little information about the difference of endothelial function between small distal pulmonary artery (PA) and large proximal PA and their contribution to the development of pulmonary hypertension. Herein, we investigate endothelium‐dependent relaxation in different orders of PAs and examine the molecular mechanisms by which chronic hypoxia attenuates endothelium‐dependent pulmonary vasodilation, leading to pulmonary hypertension. Methods and Results Endothelium‐dependent relaxation in large proximal PAs (second order) was primarily caused by releasing NO from the endothelium, whereas endothelium‐dependent hyperpolarization (EDH)–mediated vasodilation was prominent in small distal PAs (fourth–fifth order). Chronic hypoxia abolished EDH‐mediated relaxation in small distal PAs without affecting smooth muscle–dependent relaxation. RNA‐sequencing data revealed that, among genes related to EDH, the levels of Cx37 , Cx40 , Cx43 , and IK were altered in mouse pulmonary endothelial cells isolated from chronically hypoxic mice in comparison to mouse pulmonary endothelial cells from normoxic control mice. The protein levels were significantly lower for connexin 40 (Cx40) and higher for connexin 37 in mouse pulmonary endothelial cells from hypoxic mice than normoxic mice. Cx40 knockout mice exhibited significant attenuation of EDH‐mediated relaxation and marked increase in right ventricular systolic pressure. Interestingly, chronic hypoxia led to a further increase in right ventricular systolic pressure in Cx40 knockout mice without altering EDH‐mediated relaxation. Furthermore, overexpression of Cx40 significantly decreased right ventricular systolic pressure in chronically hypoxic mice. Conclusions These data suggest that chronic hypoxia‐induced downregulation of endothelial Cx40 results in impaired EDH‐mediated relaxation in small distal PAs and contributes to the development of pulmonary hypertension.

Neutral endopeptidase inhibition attenuates development of hypoxic pulmonary hypertension in rats

1993 ◽  
Vol 75 (4) ◽  
pp. 1615-1623 ◽  
Author(s):  
J. R. Klinger ◽  
R. D. Petit ◽  
R. R. Warburton ◽  
D. S. Wrenn ◽  
F. Arnal ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Pulmonary Arteries ◽  
Systolic Pressure ◽  
Weight Ratio ◽  
Neutral Endopeptidase ◽  
Mrna Levels ◽  
Hypoxic Pulmonary Hypertension ◽  
Ventricular Systolic Pressure ◽  
Nep Inhibition

Neutral endopeptidase (NEP) inhibition is thought to blunt hypoxic pulmonary hypertension by reducing atrial natriuretic peptide (ANP) metabolism, but this hypothesis has not been confirmed. We measured NEP activity, guanosine 3',5'-cyclic monophosphate (cGMP) production, plasma ANP levels, and cardiac ANP synthesis in rats given an orally active NEP inhibitor (SCH-34826) during 3 wk of hypoxia. Under normoxic conditions, SCH-34826 had no effect on plasma ANP levels but reduced pulmonary and renal NEP activity by 50% and increased urinary cGMP levels (60 +/- 6 vs. 22 +/- 4 pg/mg creatinine; P < 0.05). Under hypoxic conditions, SCH-34826-treated rats had lower plasma ANP levels (1,259 +/- 361 vs. 2,101 +/- 278 pg/ml; P < 0.05), lower right ventricular systolic pressure (53 +/- 5 vs. 73 +/- 2 mmHg; P < 0.05), lower right ventricle weight-to-left ventricle+septum weight ratio (0.47 +/- 0.04 vs. 0.53 +/- 0.03; P < 0.05), and less muscularization and percent medial wall thickness of peripheral pulmonary arteries (22 +/- 5 vs. 45 +/- 8% and 17 +/- 1 vs. 25 +/- 1%, respectively; P < 0.05 for all values) than did rats treated with vehicle alone. These values were not affected by SCH-34826 under normoxic conditions. SCH-34826 decreased right ventricular ANP tissue levels in hypoxic rats (27 +/- 10 vs. 8 +/- 1 ng/mg protein; P < 0.05) but did not affect steady-state ANP mRNA levels. We conclude that NEP inhibition blunts pulmonary hypertension without increasing plasma ANP levels.(ABSTRACT TRUNCATED AT 250 WORDS)

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