Myocardial fibrosis: role of ventricular systolic pressure, arterial hypertension, and circulating hormones

1991 ◽  
pp. 25-31 ◽  
Author(s):  
K. T. Weber ◽  
C. G. Brilla ◽  
J. S. Janicki ◽  
H. K. Reddy ◽  
S. E. Campbell
Keyword(s):  
Arterial Hypertension ◽  
Myocardial Fibrosis ◽  
Systolic Pressure ◽  
Ventricular Systolic Pressure

scholarly journals The angiopietin-1–Tie2 pathway prevents rather than promotes pulmonary arterial hypertension in transgenic mice

2009 ◽  
Vol 206 (10) ◽  
pp. 2221-2234 ◽  
Author(s):  
Lakshmi Kugathasan ◽  
Julie Basu Ray ◽  
Yupu Deng ◽  
Effat Rezaei ◽  
Daniel J. Dumont ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Transgenic Mice ◽  
Arterial Hypertension ◽  
Systolic Pressure ◽  
Endothelial Activation ◽  
Pulmonary Hemodynamics ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial ◽  
Deficient Mice

The role of the angiopoietin-1 (Ang1)–Tie2 pathway in the pathogenesis of pulmonary arterial hypertension (PAH) is controversial. Although Ang1 is well known to prevent endothelial activation and injury in systemic vascular beds, this pathway has been suggested to mediate pulmonary vascular remodeling in PAH. Therefore, we used transgenic models to determine the effect of increased or decreased Tie2 activity on the development of PAH. We now report modest spontaneous elevation in right ventricular systolic pressure in Tie2-deficient mice (Tie2+/−) compared with wild-type (WT) littermate controls, which was exacerbated upon chronic exposure to the clinically relevant PAH triggers, serotonin (5-HT) or interleukin-6 (IL-6). Moreover, overexpression of Ang1 in transgenic mice had no deleterious effect on pulmonary hemodynamics and, if anything, blunted the response to 5-HT. Exposure to 5-HT or IL-6 also decreased lung Ang1 expression, further reducing Tie2 activity and inducing pulmonary apoptosis in the Tie2+/− group only. Similarly, cultured pulmonary artery endothelial cells subjected to Tie2 silencing demonstrated increased susceptibility to apoptosis after 5-HT treatment. Finally, treatment of Tie2-deficient mice with Z-VAD, a pan-caspase inhibitor, prevented the pulmonary hypertensive response to 5-HT. Thus, these findings firmly establish that endothelial survival signaling via the Ang1–Tie2 pathway is protective in PAH.

Effects of Crocin on CCL2/CCR2 Inflammatory Pathway in Monocrotaline-Induced Pulmonary Arterial Hypertension Rats

2021 ◽  
pp. 1-19
Author(s):  
Yanling Sheng ◽  
Xiaowei Gong ◽  
Jing Zhao ◽  
Yan Liu ◽  
Yadong Yuan
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Stress Responses ◽  
Systolic Pressure ◽  
Pathological Feature ◽  
Arterial Remodeling ◽  
Inflammatory Pathway ◽  
Ventricular Systolic Pressure ◽  
Rat Models ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a malignant cardiopulmonary disease, in which pulmonary arterial remodeling is regarded as the prominent pathological feature. So far, the mechanism of PAH is still unclear, so its treatment remains a challenge. However, inflammation plays an important part in the occurrence and progression of PAH. It is well known that crocin has anti-inflammatory properties, so we investigated whether crocin could be a potential drug for the treatment of PAH rat models. Rats injected subcutaneously with monocrotaline (MCT) were treated with crocin via a gastric tube daily for four weeks. The results showed that crocin treatment significantly reduced the right ventricular systolic pressure (RVSP) and mean pulmonary artery pressure (mPAP) in the PAH rat models. Moreover, crocin treatment reduced the proliferation of pulmonary arteriole smooth muscle cells (PASMCs). In addition, crocin treatment not only relieved inflammatory cell infiltration and collagen fiber hyperplasia in the lung and right ventricle, but also decreased the expression of the CCL2/CCR2 inflammatory pathway in the lung of PAH rat models. Furthermore, crocin treatment reduced the inflammatory cytokines and oxidative stress responses. In summary, crocin may play a protective role in MCT-induced PAH rats by alleviating inflammatory response, improving pulmonary arterial remodeling, and preventing PAH. Therefore, crocin as a new treatment for PAH may be quite worthy of consideration.

Role of reflexes following myocardial necrobiosis

1965 ◽  
Vol 209 (6) ◽  
pp. 1081-1088 ◽  
Author(s):  
G. Ascanio ◽  
F. Barrera ◽  
E. V. Lautsch ◽  
M. J. Oppenheimer
Keyword(s):  
Peripheral Resistance ◽  
Systolic Pressure ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Hemodynamic Changes ◽  
Ventricular Systolic Pressure ◽  
Arterial Blood ◽  
Bilateral Vagotomy ◽  
Left Ventricular Systolic Pressure

Intracoronary administration of hexachlorotetrafluorobutane (Hexa) into non-thoracotomized dogs produced a statistically significant decrease in left ventricular systolic pressure (LVSP), mean femoral arterial blood pressure (MFAP), first derivative of left ventricular pressure pulse (dP/d t), total peripheral resistance (TPR), and cardiac output (C.O.) lasting up to 1 hr after injection. Femoral vascular resistance decreased during the first 3 min after production of necrobiosis. Fifty percent of the dogs died of ventricular fibrillation (VF) after Hexa infarction. Prereserpinized dogs did not show significant changes in the parameters which were significantly changed in normal dogs after Hexa necrobiosis except in the case of VF which was almost absent in this group. Bilateral vagotomy prior to Hexa administration prevented most hemodynamic changes after necrobiosis whereas atropine did not. Bilateral vagotomy and atropine 1 hr after necrobiosis increased MFAP, dP/d t, LVSP, C.O., and TPR. Apparently excitatory efferent sympathetic activity on heart and femoral arterial vessels is reflexly inhibited by the effects of intracoronary injection of Hexa. The afferent pathway is via the vagus nerve.

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.

Involvement of Rho kinase in the pathogenesis of acute pulmonary embolism-induced polystyrene microspheres in rats

2010 ◽  
Vol 298 (3) ◽  
pp. L297-L303 ◽  
Author(s):  
M. Toba ◽  
T. Nagaoka ◽  
Y. Morio ◽  
K. Sato ◽  
K. Uchida ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Acute Pulmonary Embolism ◽  
Kinase Inhibitors ◽  
Systolic Pressure ◽  
Rho Kinase ◽  
Arterial Oxygen Tension ◽  
Arterial Oxygen ◽  
Polystyrene Microspheres ◽  
Ventricular Systolic Pressure

Acute pulmonary embolism (PE) is a life-threatening disease, and several vasoconstrictors, including endothelin-1 (ET-1), play a key role in vasoconstriction and hypoxemia during the development of PE. Rho kinase is activated by various vasoconstrictors resulting in vascular contraction and remodeling. Recent evidence has revealed an important role of Rho kinase in the pathogenesis of systemic and pulmonary vascular diseases. However, contribution of Rho kinase in PE remains unclear. We thus investigated the role of Rho kinase in the PE rat model induced by intrajugular administration of polystyrene microspheres (mean diameter, 26 μm). At 6 h following the administration of microspheres (1.5 ml/kg), right ventricular systolic pressure (RVSP) was higher in the PE than in the control rats (15.8 ± 1.6 vs. 32.9 ± 7.5 mmHg). Arterial oxygen tension was lower (92.3 ± 12.5 vs. 66.0 ± 17.7 Torr), and alveolar-arterial difference in oxygen partial pressure was higher (3.9 ± 3.8 vs. 36.5 ± 26.9 Torr) in the PE rats. Western blotting analysis revealed upregulation and downregulation in expression of vascular cell adhesion molecule-1 and endothelial nitric oxide synthase in lungs from the PE rats, respectively, and radioimmunoassay demonstrated an increase in plasma ET-1 levels. Lung Rho kinase α expression was greater in the PE rats. At 5 h following administration of microspheres (0.75 ml/kg), intravenous Rho kinase inhibitors HA1077 and Y27632 (3 mg/kg each) attenuated elevation of RVSP (22.0 ± 3.7, 17.1 ± 3.2, 14.3 ± 2.6 mmHg, PE, PE+HA1077, PE+Y27632) and the severity of hypoxemia (66.3 ± 16.2, 94.9 ± 23.0, 89.1 ± 8.5 Torr, PE, PE+HA1077, PE+Y27632) in the PE rats. These results suggest that pulmonary endothelial dysfunction and activation of Rho kinase may contribute to the potentiation of vasoconstriction and hypoxemia in the PE rats.

ID: 113: THE ENDOTHELIAL PHD2/HIF-2 AXIS REGULATES PULMONARY ARTERY PRESSURE IN MICE

2016 ◽  
Vol 64 (4) ◽  
pp. 961.2-962
Author(s):  
PP Kapitsinou ◽  
G Rajendran ◽  
L Astleford ◽  
MP Schonfeld ◽  
M Michael ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pulmonary Artery ◽  
Right Ventricular ◽  
Oxygen Sensor ◽  
Acute Hypoxia ◽  
Systolic Pressure ◽  
Clinical Problem ◽  
Ventricular Systolic Pressure

BackgroundPulmonary hypertension (PH), a common clinical problem characterized by increased pulmonary artery (PA) pressure, is frequently triggered by hypoxia. Key mediators of cellular hypoxia responses are hypoxia-inducible factors (HIF)-1 and -2, the activity of which is regulated by prolyl-4-hydroxylase domain (PHD) proteins, with PHD2 being the main oxygen sensor that controls HIF activity under normoxia. Although both transcription factors are expressed in the lung, little is known about their cell type-specific roles in the pathogenesis of PH.Methods and ResultsHere we used a genetic approach to investigate the role of endothelial PHD2/HIF axis in the regulation of PA pressure. Endothelial cell specific HIF activation was achieved by crossing Vecadherin (Cdh5)-Cre transgenics to Phd2 floxed mice (ePhd2), while the contribution of each HIF isoform was assessed by generating double mutants lacking Phd2 and Hif-2 (ePhd2Hif2) or Phd2 and Hif-1 (Phd2Hif1). Right ventricular systolic pressure (RVSP) was measured via insertion of a 1.4F Mikro-tip catheter transducer into a surgically exposed right internal jugular vein. ePhd2 mice showed activation of HIF-signaling as shown by immunoblot analysis of lung tissue for HIF-1 and HIF-2. These mice developed spontaneous PH (RVSP, ePhd2: 54.3±6.9 vs Cre-: 24.8±2.2 mm Hg, P=0.005), which was associated with right ventricular hypertrophy (RVH) (Fulton Index, ePhd2: 0.52 vs Cre-: 0.28, P=0.0004) and early mortality. While morphologic analysis of ePhd2 lungs did not demonstrate plexiform or lumen-obliterating lesions, enhanced muscularization of peripheral PAs was detected in mutants compared to controls, as indicated by an increase in the number of arteries with diameters <100 µm that stained positive for αSMA (22.1±1.6 vs. 7.6±1.5 muscularized vessels/10 hpf, P<0.0001). The PH phenotype was maintained in ePhd2Hif1 mutants but was reversed in ePhd2Hif2 mutants. To assess the contribution of endothelial HIF-2 in hypoxia induced PH, endothelial Hif2 single mutants or Cre-littermates were exposed to normobaric hypoxia (10% O2) for 4 weeks. In contrast to controls, eHif2 mutants were protected from development of PH and RVH. Bone marrow transplantation studies showed no contribution from hematopoietic HIF-2 in hypoxia induced PH. Because hypoxia regulates endothelin 1 (EDN1), a potent vasoconstrictor but also apelin (APLN), a vasodilatory peptide acting through binding to the apelin G-protein-coupled receptor (APLNR), we assessed the role of endothelial HIF-2 axis in the regulation of these molecules. Endothelial deletion of Phd2 resulted in 6.4-fold induction of pulmonary Edn1 mRNA (P=0.029), but not Apln mRNA. In contrast, Aplnr was downregulated by 2.5-fold in ePhd2 mutants (P=0.037). A similar pattern of expression was detected in ePhd2Hif1 mice, whereas simultaneous deletion of Hif2a and Phd2 reversed these changes. To investigate the differences between acute and chronic hypoxia, we examined the effects of acute HIF activation on Edn1 and Apln/Aplnr gene expression in vivo. To model acute hypoxia, we subjected WT mice to 8% O2 for 48 hrs and maintained controls in room air. Acute hypoxia resulted in a 4.3-fold and 1.6-fold up-regulation of Edn1 and Apln transcripts respectively (P=0.0011 for Edn1, P=0.08 for Apln) while Aplnr was reduced by 4.3-fold (P=0.0005). We observed similar gene expression changes in mice treated with a prolyl-4-hydroxylase inhibitor (PHI) that results in global HIF activation.ConclusionsOur studies identify endothelial HIF-2 as a key transcription factor in the pathogenesis of PH and suggest that HIF-2 regulates PA pressure by modulating the expression of vasoactive molecules. Our findings identify the PHD2/HIF2 axis as a potential target for PH therapies.

scholarly journals Baicalin prevents pulmonary arterial remodeling in vivo via the AKT/ERK/NF-κB signaling pathways

2019 ◽  
Vol 9 (4) ◽  
pp. 204589401987859 ◽  
Author(s):  
Guosen Yan ◽  
Jinxia Wang ◽  
Tao Yi ◽  
Junfen Cheng ◽  
Haixu Guo ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Signaling Pathways ◽  
Vascular Remodeling ◽  
Systolic Pressure ◽  
Pulmonary Vascular Remodeling ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial

Pulmonary arterial hypertension is a rapidly progressive and often fatal disease. As the pathogenesis of pulmonary arterial hypertension remains unclear, there is currently no good drug for pulmonary arterial hypertension and new therapy is desperately needed. This study investigated the effects and mechanism of baicalin on vascular remodeling in rats with pulmonary arterial hypertension. A rat pulmonary arterial hypertension model was constructed using intraperitoneal injection of monocrotaline, and different doses of baicalin were used to treat these rats. The mean pulmonary arterial pressure (mPAP) and right ventricular systolic pressure (RVSP) were measured with a right heart catheter. Moreover, the hearts were dissected to determine the right ventricular hypertrophy index (RVHI). The lung tissues were stained with H&E and Masson's staining to estimate the pulmonary vascular remodeling and collagen fibrosis, and the expression of proteins in the AKT, ERK, and NF-κB p65 phosphorylation (p-AKT, p-ERK, p-p65) was examined by Western blot analysis. We found that compared with untreated pulmonary arterial hypertension rats, baicalin ameliorated pulmonary vascular remodeling and cardiorespiratory injury, inhibited p-p65 and p-ERK expression, and promoted p-AKT and p-eNOS expression. In conclusion, baicalin interfered with pulmonary vascular remodeling and pulmonary arterial hypertension development in rats through the AKT/eNOS, ERK and NF-κB signaling pathways.

scholarly journals Leptin signalling system as a target for pulmonary arterial hypertension therapy

2015 ◽  
Vol 45 (4) ◽  
pp. 1066-1080 ◽  
Author(s):  
Alice Huertas ◽  
Ly Tu ◽  
Raphaël Thuillet ◽  
Morane Le Hiress ◽  
Carole Phan ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
Perivascular Inflammation ◽  
Current Therapies ◽  
Pulmonary Arterial ◽  
Anti Inflammatory ◽  
Pulmonary Arterial Hypertension Therapy

Excessive proliferation of pulmonary arterial smooth muscle cells (PA-SMCs) and perivascular inflammation lead to pulmonary arterial hypertension (PAH) progression, but they are not specifically targeted by the current therapies. Since leptin (Ob) and its main receptor ObR-b contribute to systemic vascular cell proliferation and inflammation, we questioned whether targeting Ob/ObR-b axis would be an effective antiproliferative and anti-inflammatory strategy against PAH.In idiopathic PAH (iPAH), using human lung tissues and primary cell cultures (early passages ≤5), we demonstrate that pulmonary endothelial cells (P-ECs) over produce Ob and that PA-SMCs overexpress ObR-b. Furthermore, we obtain evidence that Ob enhances proliferation of human PA-SMCs in vitro and increases right ventricular systolic pressure in Ob-treated mice in the chronic hypoxia-induced pulmonary hypertension (PH) model. Using human cells, we also show that Ob leads to monocyte activation and increases cell adhesion molecule expression levels in P-ECs. We also find that Ob/ObR-b axis contributes to PH susceptibility by using ObR-deficient rats, which display less severe hypoxia-induced PH (pulmonary haemodynamics, arterial muscularisation, PA-SMC proliferation and perivascular inflammation). Importantly, we demonstrate the efficacy of two curative strategies using a soluble Ob neutraliser and dichloroacetate in hypoxia-induced PH.We demonstrate here that Ob/ObR-b axis may represent anti-proliferative and anti-inflammatory targets in PAH.

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