scholarly journals LRP1 Deficiency in Vascular SMC Leads to Pulmonary Arterial Hypertension That Is Reversed by PPARγ Activation

2019 ◽  
Vol 124 (12) ◽  
pp. 1778-1785 ◽  
Author(s):  
Laurent Calvier ◽  
Philippe Boucher ◽  
Joachim Herz ◽  
Georg Hansmann
Keyword(s):  
Growth Factor ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Main Pulmonary Artery ◽  
Tissue Growth ◽  
Pulmonary Vasculature ◽  
Pparγ Agonist ◽  
Pulmonary Arterial ◽  
Human Pulmonary Artery

Rationale: Arterial remodeling—a hallmark of many cardiovascular pathologies including pulmonary arterial hypertension (PAH)—is regulated by TGFβ1 (transforming growth factor-β1)–TGFβ receptors and the antagonistic, vasoprotective BMPR2 (bone morphogenetic protein receptor 2)–PPARγ (peroxisome proliferator–activated receptor-γ) axis. However, it is unclear which factors drive detrimental TGFβ1 pathways in the hypertensive pulmonary vasculature. Objective: We hypothesized that LRP1 (low-density lipoprotein receptor–related protein 1) expression is decreased in PAH, leading to enhancement (disinhibition) of TGFβ1 signals and that the PPARγ agonist pioglitazone can restore vascular homeostasis and prevent PAH resulting from LRP1 deletion in vascular smooth muscle cells (SMCs). Methods and Results: Targeted deletion of LRP1 in vascular SMC (smLRP1 −/− ) in mice disinhibited TGFβ1–CTGF (connective tissue growth factor) signaling, leading to spontaneous PAH and distal pulmonary arterial muscularization as assessed by closed-chest cardiac catheterization and anti-αSMA staining. Pioglitazone inhibited the canonical TGFβ1–CTGF axis in human pulmonary artery SMC and smLRP1 −/− main pulmonary artery (CTGF and NOX4) and reversed PAH in smLRP1 −/− mice. TGFβ1 boosted pSmad3 in PASMC from smLRP1 −/− mice versus controls. Pioglitazone-activated PPARγ binds to Smad3 in human pulmonary artery SMC (coimmunoprecipitation), thereby blocking its phosphorylation and overriding LRP1 deficiency. Finally, mRNA and protein expression of LRP1 was decreased in pulmonary plexiform lesions of patients with end-stage idiopathic PAH (laser capture microdissection, qPCR, and immunohistochemistry). Downregulation of LRP1 protein was also demonstrated in explanted PASMC from patients with PAH and accompanied by enhanced TGFβ1–pSmad3–CTGF signaling and increased TGFβ1–induced PASMC proliferation that was prevented by pioglitazone. Conclusions: Here, we identify LRP1 as an integrator of TGFβ1–mediated mechanisms that regulate vascular remodeling in mice and clinical PAH and PPARγ as a therapeutic target that controls canonical TGFβ1 pathways. Hence, pharmacologic PPARγ activation represents a promising new therapy for patients with PAH who lack the vasoprotective LRP1 in vascular SMC.

Safflower injection inhibits pulmonary arterial remodeling in a monocrotaline-induced pulmonary arterial hypertension rat model

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Aifeng Chen ◽  
Shibiao Ding ◽  
Liangliang Kong ◽  
Jianpu Xu ◽  
Fei He ◽  
...  
Keyword(s):  
Growth Factor ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Cardiac Muscle ◽  
Rat Model ◽  
Dependent Manner ◽  
Arterial Remodeling ◽  
Pulmonary Arterial ◽  
Dose Dependent

AbstractPulmonary arterial hypertension (PAH) is a group of diseases with an increase of pulmonary artery pressure (PAP) and pulmonary vascular resistance. Here, the effects of safflower injection, a preparation of Chinese herbs, was investigated in a monocrotaline (MCT)-induced PAH rat model. PAP, carotid artery pressure (CAP), and the right ventricular hypertrophy index (RVHI) increased in the PAH group, while safflower injection was able to inhibit this increase to similar levels as observed in the normal group. The arteriole wall of the lungs and cardiac muscle were thickened and edema was observed in the PAH group, while these pathologies were improved in the herb-treated group in a dose-dependent manner. MCT treatment induced proliferation of pulmonary artery smooth muscle cells (PASMCs), which was inhibited by safflower injection in a dose-dependent manner. Our experimental results demonstrated that safflower injection can regulate pulmonary arterial remodeling through affecting the expression of connective tissue growth factor, transforming growth factor-β, integrin, collagen or fibronectin, which subsequently affected the thicknesses of the arteriole walls of the lungs and cardiac muscle, and thereby benefits the control of PAH. This means safflower injection improved the abnormalities in PAP, CAP and RVHI, and pulmonary arterial remodeling through regulation of remodeling factors.

Abstract 18587: Downregulation of Pulmonary Artery Endothelial Catechol-o-methyltransferase Activity by Aldosterone Increases Norepinephrine Levels in Pulmonary Arterial Hypertension

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Samantha Torquato ◽  
Kiyotake Ishikawa ◽  
Jaume Aguerro ◽  
Bradley A Maron ◽  
Joseph Loscalzo ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Right Heart Failure ◽  
Therapeutic Interventions ◽  
Pulmonary Vasculature ◽  
Methyltransferase Activity ◽  
Comt Activity ◽  
Pulmonary Arterial

Elevated levels of norepinephrine (NE) occur in pulmonary arterial hypertension (PAH) and are determined, in part, by the activity of catechol- O -methyltransferase (COMT). COMT degrades catecholamines, is negatively regulated by calcium, and is expressed by pulmonary artery endothelial cells (PAEC). As hyperaldosteronism occurs in PAH and aldosterone (ALDO) influences calcium levels, we hypothesized that ALDO decreases COMT activity to increase NE levels in PAH. Accordingly, human PAEC were treated with ALDO (10 -7 mol/L), a level that is achieved clinically in PAH, for up to 72 h. Compared to vehicle-treated PAEC, ALDO decreased COMT activity by 59.2 ± 6.2% (p<0.01) to increase NE levels in the medium (122.4 ± 11.8 vs. 210.7 ± 15.5 pg/mL/mg protein, p<0.01). This occurred as a result of an ALDO-mediated decrease in COMT protein expression by 52.6 ± 9.3% (p<0.01) as well as an increase in intracellular calcium levels (102.9 ± 21.0 vs. 167.7 ± 17.8 nmol/L, p<0.05) to inhibit activity. These effects were abrogated by coincubation with spironolactone. To determine the in vivo relevance of these findings, COMT was examined in the rat monocrotaline model of PAH with confirmed hyperALDO. COMT was decreased (47.6 ± 10.2 %control, p<0.05) in remodeled pulmonary arterioles with a concomitant increase in lung NE levels (432.8 ± 44.5 vs. 899.7 ± 34.2 pg/mL, p<0.01) compared to control rats. In the porcine pulmonary vein banding model of pulmonary hypertension (PH-pigs) with elevated mean pulmonary artery pressure (15[13-15] vs. 35[27-43], p<0.01) and pulmonary vascular resistance (PVR) index (1.97[1.74-2.28] vs. 5.78[2.61-8.75], p <0.05), ALDO levels were also increased (27.1 ± 5.1 vs. 60.8 ± 10.6 pg/mL, p<0.03) in advance of right heart failure as compared to sham controls. PH-pigs demonstrated a 48.3 ± 9.9% (p<0.02) decrease in pulmonary vascular COMT expression and an increase in NE levels (114.6 ± 20.2 vs. 1,622.6 ± 489.2 pg/mL, p<0.02) that correlated positively with ALDO levels (R 2 =0.58, p<0.02). These findings were confirmed in patients with PAH. Together, these data indicate that there is crosstalk in the pulmonary vasculature between ALDO and the sympathetic nervous system to regulate NE levels in PAH, and thus, have implications for therapeutic interventions.

scholarly journals Early onset of retrograde flow in the main pulmonary artery is a characteristic of pulmonary arterial hypertension

2011 ◽  
Vol 33 (6) ◽  
pp. 1362-1368 ◽  
Author(s):  
Frank Helderman ◽  
Gert-Jan Mauritz ◽  
Kirsten E. Andringa ◽  
Anton Vonk-Noordegraaf ◽  
J. Tim Marcus
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Early Onset ◽  
Main Pulmonary Artery ◽  
Retrograde Flow ◽  
Pulmonary Arterial

Regional Biomechanical and Microstructural Alterations of the Ovine Main Pulmonary Artery During Postnatal Growth

2012 ◽  
Author(s):  
Bahar Fata ◽  
Christopher A. Carruthers ◽  
Gregory A. Gibson ◽  
Simon C. Watkins ◽  
Danielle Gottlieb ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Congenital Heart ◽  
Main Pulmonary Artery ◽  
Postnatal Growth ◽  
Tissue Mechanics ◽  
Microstructural Alterations ◽  
Native Tissue ◽  
Pulmonary Arterial

It has been estimated that worldwide 600,000 babies are born annually with significant congenital heart disease (1). Congenital heart and related vascular defects cause increased flow and pulmonary pressure leading to unfavorable vascular remodeling that results in pulmonary arterial hypertension (1). Developing tissue engineered replacements that mimic the growth and remodeling behavior of native tissue is the optimal approach in treatment of congenital arterial anomalies. The understanding of the underlying mechanisms leading to pulmonary arterial hypertension as well as replicating native pulmonary artery functionality in engineered replacements requires knowledge of native tissue mechanics and growth behavior. In the present study, we report novel information on the changes in the structure-mechanics behavior of the growing pulmonary artery.

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