Overview of Current Therapeutic Approaches for Pulmonary Hypertension

Stamm, Jason; Risbano, Michael G.; Mathier, Michael A.

doi:10.4103/2045-8932.83444

Cited by 45 publications

(29 citation statements)

References 188 publications

(318 reference statements)

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“…PH results in right ventricular hypertrophy (RVH), progressive fibrosis and RV failure; and low cardiac output leading to increase morbidity, and mortality [5], [6]. In the clinical setting, the disease is often detected in later stages marked by full-blown RV failure and, the treatment regimen is limited that includes the use of prostaglandin analogues, endothelin receptor antagonist and PDE5 which works primarily in the vasculature as a vasodilator and anti-proliferative [7], [8], [9]. The pathological manifestation of PH is remodeling of pulmonary arteries which increased proliferation of pulmonary artery smooth muscle cells and dysfunction of pulmonary artery endothelial cells resulting gross vascular remodeling.…”

Section: Introductionmentioning

confidence: 99%

Circulating miRNAs as Potential Marker for Pulmonary Hypertension

et al. 2013

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MircoRNAs (miRNAs) are small non-coding RNAs that govern the gene expression and, play significant role in the pathogenesis of heart failure. The detection of miRNAs in circulation of pulmonary hypertensive (PH) human subjects remains elusive. In the current study, we determined the pattern of miRNAs of mild-to-severe human PH subjects and, compared them with the control subjects by miRNA array. Blood was obtained using fluoroscopic and waveform guided catheterization from the distal (pulmonary artery) port of the catheter. A total 40 human subjects were included in the study and, the degree of PH was determined by mean pulmonary arterial pressure. Among several miRNAs in the array, we validated 14 miRNAs and, the data were consistent with the array profile. We identified several novel downregulated miRNAs (miR-451, miR-1246) and upregulated miRNAs (miR-23b, miR-130a and miR-191) in the circulation of PH subjects. Our study showed novel set of miRNAs which are dysregulated in PH and, are directly proportional to the degree of PH. These miRNAs may be considered as potential biomarker for early detection of PH.

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Section: Introductionmentioning

confidence: 99%

Circulating miRNAs as Potential Marker for Pulmonary Hypertension

et al. 2013

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“…Drugs used to manage pulmonary hypertension are traditionally designed to target the vasculature and enhance vasodilator and antiproliferation pathways, including nitric oxide/cyclic guanosine monophosphate (with phosphodiesterase type 5 inhibitors) and prostacyclin (with prostacyclin and related mimetics), and/or inhibit vasoconstrictor pathways, such as endothelin 1 (with receptor antagonists). 1,2 However, it is increasingly recognized that, in addition to the pulmonary vasculature, the right heart is a viable therapeutic target in the treatment of pulmonary hypertension. 3,4 We have recently shown, using a hypoxia model of pulmonary hypertension in rats, that GW0742, a ligand for peroxisome proliferator-activated receptor (PPAR) β/δ, 5 reduces right heart hypertrophy without influencing pulmonary vascular remodeling.…”

Section: Introductionmentioning

confidence: 99%

The Peroxisome Proliferator–Activated Receptor β/δ Agonist GW0742 has Direct Protective Effects on Right Heart Hypertrophy

et al. 2013

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Pulmonary hypertension is a debilitating disease with no cure. We have previously shown that peroxisome proliferator-activated receptor (PPAR) β/δ agonists protect the right heart in hypoxia-driven pulmonary hypertension without affecting vascular remodeling. PPARβ/δ is an important receptor in lipid metabolism, athletic performance, and the sensing of prostacyclin. Treatment of right heart hypertrophy and failure in pulmonary hypertension is an emerging target for future therapy. Here we have investigated the potential of GW0742, a PPARβ agonist, to act directly on the right heart in vivo and what transcriptomic signatures are associated with its actions. Right heart hypertrophy and failure was induced in mice using a pulmonary artery banding (PAB) model. GW0742 was administered throughout the study. Cardiovascular parameters were measured using echocardiography and pressure monitoring. Fibrosis and cellular changes were measured using immunohistochemistry. Transcriptomics were measured using the Illumina MouseRef-8v3 BeadChip array and analyzed using GeneSpring GX (ver. 11.0). PAB resulted in right heart hypertrophy and failure and in increased fibrosis. GW0742 reduced or prevented the effects of PAB on all parameters measured. GW0742 altered a number of genes in the transcriptome, with Angptl4 emerging as the top gene altered (increased) in animals with PAB. In conclusion, the PPARβ/δ agonist GW0742 has direct protective effects on the right heart in vivo. These observations identify PPARβ/δ as a viable therapeutic target to treat pulmonary hypertension that may complement current and future vasodilator drugs.

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“…of PAH, few effective therapeutic modalities have emerged as a result (2,3). Dichloroacetate (DCA) is as a metabolism modulator, which has been utilized for approximately three decades as the first line drug in the treatment of diseases associated with mitochondrial dysfunction, including congenital lactic acidosis (4).…”

Section: Dichloroacetate Prevents But Not Reverses the Formation Of Nmentioning

confidence: 99%

Dichloroacetate prevents but not reverses the formation of neointimal lesions in a rat model of severe pulmonary arterial hypertension

Yan

Shen

et al. 2014

Molecular Medicine Reports

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The formation of neointimal lesions is one of the characteristic pathological alterations of the pulmonary vasculature in response to sustained pulmonary arterial hypertension (PAH). To date, the effect of dichloroacetate (DCA) on these intimal lesions had remained to be investigated. In the present study, the beneficial impact of DCA on the formation of neointimal lesions was examined in rats treated with monocrotaline following pneumonectomy. The rats were subjected to monocrotaline subcutaneous injection seven days following left pneumonectomy and received DCA by gastric gavage (80 mg/kg/day) for 20 days. At the end of the experiments, hemodynamic measurement was performed prior to the excision of the rats' right lungs for further morphometric and immunoblot analysis. Furthermore, the activity of reactive oxygen species (ROS), superoxide dismutase (SOD) in the lungs was examined by a colorimetric assay. The results revealed that DCA treatment from day 8-28 following pneumonectomy caused a marked reduction in pulmonary arterial pressure and amelioration in right ventricle hypertrophy (mean pulmonary arterial pressure, 24±2.8 vs. 33±5.5 mmHg; right ventricle-to-left ventricle + intra-ventricle septum ratio, 29±2.8 vs. 43±3.3%; P<0.05) and pulmonary arterioles intimal proliferation (grade 1 and 2 occlusion, 24 and 20% vs. 44 and 40%; P<0.05) in pulmonary hypertensive rats. By contrast, DCA treatment initiated 29 days following pneumonectomy did not result in any improvement in pulmonary circulatory parameters or regression of occlusive neointimal lesions. Immunohistochemical and immunoblot assays demonstrated markedly reduced hypoxia inducible factor (HIF-1α) levels, and increased voltage-dependent potassium channel subtype 1.5 (Kv1.5) expression levels were observed in those neointimal regions in rats receiving DCA preventive therapy. Furthermore, preventive treatment with DCA significantly increased the activity of copper/zinc superoxide dismutase (Cu/Zn SOD activity, 88±4.2 vs. 53±2.7 U/mgprot; P<0.05) and promoted the degradation of ROS (106±4.7 vs. 79±13.3 U/mgprot; P<0.05), which was compromised in the delayed intervention group. Therefore, DCA is effective to prevent the formation of intimal lesions, which may be attributed to the induction of the upregulation of Cu/Zn SOD activity and the suppression of HIF-1α activation.

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Overview of Current Therapeutic Approaches for Pulmonary Hypertension

Cited by 45 publications

References 188 publications

Circulating miRNAs as Potential Marker for Pulmonary Hypertension

Circulating miRNAs as Potential Marker for Pulmonary Hypertension

The Peroxisome Proliferator–Activated Receptor β/δ Agonist GW0742 has Direct Protective Effects on Right Heart Hypertrophy

Dichloroacetate prevents but not reverses the formation of neointimal lesions in a rat model of severe pulmonary arterial hypertension

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