Development Of Right Ventricular Hypertrophy Research Articles

Electrocardiographic Diagnosis of Right Ventricular Hypertrophy: a Literature Review

The development of right ventricular hypertrophy (RVH) is a consequence of a large group of diseases that lead to increased pressure or volume load on the right ventricle. Electrocardiography (ECG) is a commonly used diagnostic method in clinical practice. This method allows for the identification of RVH signs in the early stages of examination. During the 20th century, more than 30 diagnostic criteria were developed. Several of these criteria are associated with worse prognosis, including increased mortality. Authors of international guidelines recommend the verification of criteria in local populations. Such studies have not been published in Russia, but according to data obtained from foreign researchers, the diagnostic properties of ECG criteria can vary significantly. In most cases, the criteria are characterized by low sensitivity and high specificity, which complicates early diagnosis of conditions leading to RVH development. It is proposed to increase the sensitivity of the method by using all the developed criteria or sets that include some of them. However, this approach may reduce the specificity of ECG diagnosis of RVH, and the selection of criteria for inclusion in diagnostic algorithms is not always based on scientific research data. This article analyzes the history of the development of RVH criteria, research data on their diagnostic capabilities, and ways to improve diagnostic algorithms.

Northern Pulmonary Hypertension: A Forgotten Kind of Pulmonary Circulation Pathology.

Northern pulmonary hypertension (NPH) is a medical condition that is still enigmatic in non-Russian-speaking countries. The extant previous literature is mostly available in the Russian language and, therefore, not accessible to the rest of the world. The recent increased interest in climate changes and environmental effects on pulmonary circulation prompted us to summarize the knowledge from the past about the effects of cold on pulmonary vasculature. In this review, we, for the first time, describe, in detail, the pathological attributes of human NPH, a medical disorder that occurs in people living in extremely cold regions, in the English language. Briefly, NPH is characterized by the hyper-muscularization of the pulmonary arteries and de novo muscularization of the arterioles with the ultimate development of right ventricular hypertrophy. However, the profound molecular mechanisms of the NPH pathology are to be revealed in future comprehensive studies.

Abstract 11774: Right Ventricular Function and Myocardial Blood Volume Analyses by Convolutional Neural Network in Experimental Pulmonary Hypertension

Introduction: Survival of patients with pulmonary hypertension (PH) is highly dependent on the right ventricular (RV) function. Despite the association of various factors with adaptive or maladaptive RV phenotypes, the contribution of microvascular density to RV adaptation to pressure overload remains unclear. Hypothesis: This study aimed to evaluate the RV myocardial blood volume and its role in the RV adaptation to pressure overload. Methods: Both the University Animal Care Committee and the federal authorities for animal research of the Regierungsprasidium Giessen (Hessen, Germany) approved the study protocol. The study used adult Wistar-Kyoto rats and Sprague-Dawley rats to induce PH using SuHx and monocrotaline (MCT), respectively. Echocardiography, in vivo contrast-μCT, and invasive hemodynamic measurements were performed. The researchers used an artificial intelligence (AI)-based convolutional neural network (CNN) approach to reconstruct, segment, and analyze the cardiac μCT images. The RV functional reserve was evaluated during mCT acquisition and dobutamine stress test, and metabolomics analysis was performed. Results: The data showed that SuHx rats developed maladaptive cardiac function and RV-PA uncoupling. MCT rats exhibited adaptive RV function at days 14 and 21, but maladaptive function at day 35, which was associated with RV-PA uncoupling and reduced RV functional reserve. Impaired PKA-CREB signaling pathway was also found to be associated with the reduced RV functional reserve in the MCT rats. In both PH models, the absolute RV blood volume significantly increased with the development of RV hypertrophy, but the relative blood volume decreased, which was associated with maladaptive RV function Conclusions: This study is the first to demonstrate the use of AI CNN in post-processing of μCT-derived cardiac images from experimental PH models. Additionally, a single-beat PV loop was established for the first time in a rat model of PH by combining non-invasive and invasive techniques. The findings suggest that RV maladaptive function in rat models of PH is characterized by capillary rarefaction, impaired RV reserve in response to dobutamine infusion, which is associated with impaired PKA-CREB signaling pathway in the RV.

Platelet-Derived Growth Factor Receptor Type α Activation Drives Pulmonary Vascular Remodeling Via Progenitor Cell Proliferation and Induces Pulmonary Hypertension.

BackgroundPlatelet‐derived growth factor is a major regulator of the vascular remodeling associated with pulmonary arterial hypertension. We previously showed that protein widely 1 (PW1+) vascular progenitor cells participate in early vessel neomuscularization during experimental pulmonary hypertension (PH) and we addressed the role of the platelet‐derived growth factor receptor type α (PDGFRα) pathway in progenitor cell‐dependent vascular remodeling and in PH development.Methods and ResultsRemodeled pulmonary arteries from patients with idiopathic pulmonary arterial hypertension showed an increased number of perivascular and vascular PW1+ cells expressing PDGFRα. PW1nLacZ reporter mice were used to follow the fate of pulmonary PW1+ progenitor cells in a model of chronic hypoxia–induced PH development. Under chronic hypoxia, PDGFRα inhibition prevented the increase in PW1+ progenitor cell proliferation and differentiation into vascular smooth muscle cells and reduced pulmonary vessel neomuscularization, but did not prevent an increased right ventricular systolic pressure or the development of right ventricular hypertrophy. Conversely, constitutive PDGFRα activation led to neomuscularization via PW1+ progenitor cell differentiation into new smooth muscle cells and to PH development in male mice without fibrosis. In vitro, PW1+ progenitor cell proliferation, but not differentiation, was dependent on PDGFRα activity.ConclusionsThese results demonstrate a major role of PDGFRα signaling in progenitor cell–dependent lung vessel neomuscularization and vascular remodeling contributing to PH development, including in idiopathic pulmonary arterial hypertension patients. Our findings suggest that PDGFRα blockers may offer a therapeutic add‐on strategy to combine with current pulmonary arterial hypertension treatments to reduce vascular remodeling. Furthermore, our study highlights constitutive PDGFRα activation as a novel experimental PH model.

Protective Effects of Meldonium in Experimental Models of Cardiovascular Complications with a Potential Application in COVID-19.

Right ventricular (RV) and left ventricular (LV) dysfunction is common in a significant number of hospitalized coronavirus disease 2019 (COVID-19) patients. This study was conducted to assess whether the improved mitochondrial bioenergetics by cardiometabolic drug meldonium can attenuate the development of ventricular dysfunction in experimental RV and LV dysfunction models, which resemble ventricular dysfunction in COVID-19 patients. Effects of meldonium were assessed in rats with pulmonary hypertension-induced RV failure and in mice with inflammation-induced LV dysfunction. Rats with RV failure showed decreased RV fractional area change (RVFAC) and hypertrophy. Treatment with meldonium attenuated the development of RV hypertrophy and increased RVFAC by 50%. Mice with inflammation-induced LV dysfunction had decreased LV ejection fraction (LVEF) by 30%. Treatment with meldonium prevented the decrease in LVEF. A decrease in the mitochondrial fatty acid oxidation with a concomitant increase in pyruvate metabolism was noted in the cardiac fibers of the rats and mice with RV and LV failure, respectively. Meldonium treatment in both models restored mitochondrial bioenergetics. The results show that meldonium treatment prevents the development of RV and LV systolic dysfunction by enhancing mitochondrial function in experimental models of ventricular dysfunction that resembles cardiovascular complications in COVID-19 patients.

Selective inhibition of the PI3K isoform p110alpha using BYL719 protects against tyrosine kinase-mediated processes in PASMCs and reduces experimental pulmonary hypertension in mice and rats

Abstract Rationale Pulmonary arterial hypertension (PAH) is a vascular disease characterized by chronic increases in pulmonary vascular resistance (PVR), pulmonary arterial pressure (PAP), and right ventricular (RV) hypertrophy. Increased activation of receptor tyrosine kinase (RTK) -mediated signaling pathways leads to increased proliferation and migration of pulmonary smooth vascular muscle cells (PASMCs) which promote vascular remodeling processes. We identified the catalytic subunit p110alpha of phosphatidylinositol-3-kinase as a key enzyme for these processes and showed that both genetic ablation of p110alpha in SMCs and pharmacological inhibition can prevent experimental PH. Here, the effects of the orally bioavailable p110alpha selective PI3K inhibitor BYL719 on the RTK-mediated proliferation and chemotaxis of PASMCs, as well as the effects in the hypoxia-induced mouse and in the Sugen / hypoxia (SuHx) -induced rat model of PH were investigated. Methods Human and murine PASMCs were pretreated with different concentrations of BYL719 and stimulated with a mixture of growth factors (PDGF [30ng/ml], EGF [0,5ng/ml], bFGF [2ng/ml], insulin [0,5ng/ml], and FBS [5%]). Proliferation was investigated using a BrdU incorporation ELISA assay (Roche). Chemotaxis was quantified using modified Boyden chambers. Male BL/6 mice were subjected to hypoxia (10% O2) for 21 days. Treatment with BYL719 (or vehicle) was carried out via daily gavage of 50mg/kg bodyweight. In addition, a therapeutic approach was investigated using male Sprague Dawley rats in the SuHx model, which were treated with BYL719 (20 mg / kg body weight) or vehicle for 2 weeks after a three-week hypoxia phase. The RV pressure (RVSP) was measured using a Millar® or liquid-filled catheter. The RV hypertrophy is shown as the quotient of the weights of the RV to the LV + septum (RV / (LV + S)). Results Growth factor-induced proliferation and chemotaxis of the PASMCs were significantly and concentration-dependently inhibited by BYL719. The exposure to hypoxia led to an increase of the RVSP (24.5±0.95 to 35.2±1.28 mmHg) and the development of right ventricular hypertrophy (RV / LV + S 0.24±0.01 to 0.37±0.073), which was significantly reduced in the BYL719 treated group (RVSP 31.4±0.53 mmHg; RV / LV + S 0.31±0.01) (p<0.05). In addition, SuHx led to a robust increase of the RVSP (129.2±5.4 mmHg) and pronounced RV hypertrophy (RV / (LV + S): 0.86±0.04), which were significantly reduced by the therapeutic BYL719 treatment (102.0±6.1 mmHg or 0.64±0.03). Conclusion These results show that inhibition of p110alpha using the BYL719 reduced growth factor-mediated pathological processes in PASMCs in vitro, as well as hypoxia-induced (mouse) and already established SuHx-induced PH (rat). Thus, the inhibition of p110a using BYL719 represents a promising approach for the treatment of PAH. Funding Acknowledgement Type of funding sources: None.

Lack of Contribution of p66shc to Pressure Overload-Induced Right Heart Hypertrophy.

The leading cause of death in pulmonary arterial hypertension (PAH) is right ventricular (RV) failure (RVF). Reactive oxygen species (ROS) have been suggested to play a role in the development of RV hypertrophy (RVH) and the transition to RVF. The hydrogen peroxide-generating protein p66shc has been associated with left ventricular (LV) hypertrophy but its role in RVH is unclear. The purpose of this study was to determine whether genetic deletion of p66shc affects the development and/or progression of RVH and RVF in the pulmonary artery banding (PAB) model of RV pressure overload. The impact of p66shc on mitochondrial ROS formation, RV cardiomyocyte function, as well as on RV morphology and function were studied three weeks after PAB or sham operation. PAB in wild type mice did not affect mitochondrial ROS production or RV cardiomyocyte function, but induced RVH and impaired cardiac function. Genetic deletion of p66shc did also not alter basal mitochondrial ROS production or RV cardiomyocyte function, but impaired RV cardiomyocyte shortening was observed following PAB. The development of RVH and RVF following PAB was not affected by p66shc deletion. Thus, our data suggest that p66shc-derived ROS are not involved in the development and progression of RVH or RVF in PAH.

Nox2 Upregulation and p38α MAPK Activation in Right Ventricular Hypertrophy of Rats Exposed to Long-Term Chronic Intermittent Hypobaric Hypoxia.

One of the consequences of high altitude (hypobaric hypoxia) exposure is the development of right ventricular hypertrophy (RVH). One particular type of exposure is long-term chronic intermittent hypobaric hypoxia (CIH); the molecular alterations in RVH in this particular condition are less known. Studies show an important role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex-induced oxidative stress and protein kinase activation in different models of cardiac hypertrophy. The aim was to determine the oxidative level, NADPH oxidase expression and MAPK activation in rats with RVH induced by CIH. Male Wistar rats were randomly subjected to CIH (2 days hypoxia/2 days normoxia; n = 10) and normoxia (NX; n = 10) for 30 days. Hypoxia was simulated with a hypobaric chamber. Measurements in the RV included the following: hypertrophy, Nox2, Nox4, p22phox, LOX-1 and HIF-1α expression, lipid peroxidation and H2O2 concentration, and p38α and Akt activation. All CIH rats developed RVH and showed an upregulation of LOX-1, Nox2 and p22phox and an increase in lipid peroxidation, HIF-1α stabilization and p38α activation. Rats with long-term CIH-induced RVH clearly showed Nox2, p22phox and LOX-1 upregulation and increased lipid peroxidation, HIF-1α stabilization and p38α activation. Therefore, these molecules may be considered new targets in CIH-induced RVH.

Oxidative Stress, Kinase Activity and Inflammatory Implications in Right Ventricular Hypertrophy and Heart Failure under Hypobaric Hypoxia.

High altitude (hypobaric hypoxia) triggers several mechanisms to compensate for the decrease in oxygen bioavailability. One of them is pulmonary artery vasoconstriction and its subsequent pulmonary arterial remodeling. These changes can lead to pulmonary hypertension and the development of right ventricular hypertrophy (RVH), right heart failure (RHF) and, ultimately to death. The aim of this review is to describe the most recent molecular pathways involved in the above conditions under this type of hypobaric hypoxia, including oxidative stress, inflammation, protein kinases activation and fibrosis, and the current therapeutic approaches for these conditions. This review also includes the current knowledge of long-term chronic intermittent hypobaric hypoxia. Furthermore, this review highlights the signaling pathways related to oxidative stress (Nox-derived O2.- and H2O2), protein kinase (ERK5, p38α and PKCα) activation, inflammatory molecules (IL-1β, IL-6, TNF-α and NF-kB) and hypoxia condition (HIF-1α). On the other hand, recent therapeutic approaches have focused on abolishing hypoxia-induced RVH and RHF via attenuation of oxidative stress and inflammatory (IL-1β, MCP-1, SDF-1 and CXCR-4) pathways through phytotherapy and pharmacological trials. Nevertheless, further studies are necessary.

Targeting Lysine‐specific Demethylase 1 (LSD1) in an Experimental Model of Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic disease that is characterized by abundant deposition of extracellular matrix proteins in the lungs, which ultimately leads to respiratory failure and death. The existing treatment options neither arrest disease progression nor provide significant improvement in lung function. Hence, it is essential that we identify novel targets or develop add‐on pharmacological agents to treat this fatal disease. Epithelial to mesenchymal transition (EMT) plays a key role in the pathogenesis of IPF, wherein alveolar epithelial cells lose part of their characteristics, while gaining mesenchymal markers. Inhibition of the EMT process could be a potential approach to treat lung fibrosis. Accumulating evidence suggests that inhibition of lysine‐specific demethylase 1 (LSD1), a chromatin‐modifying enzyme that regulates gene transcription prevents EMT and fibrogenesis. Here, we hypothesized that inhibition of LSD1 by tranylcypromine protects against bleomycin‐induced lung fibrosis.A single instillation of Bleomycin (Bleo; 2.5mg/Kg) in 8‐weeks old rats was used to induce lung fibrosis. Drug treatment with tranylcypromine was commenced on the same day as Bleo administration using two different doses (1mg/Kg and 2 mg/Kg ip). After two weeks, rats were instrumented to measure right ventricular systolic pressure (RVSP) and cardiac function. Bleo injected animals developed secondary pulmonary hypertension as evidenced by increase in RVSP in comparison with control rats (RVSP; 25.4±0.71 vs 52.7±2.5, mmHg) with a concomitant development of right ventricular hypertrophy (RVH; 0.27±0.01 vs 0.45±0.06). Significant attenuation of RVSP (1mg/kg: 52.7± 2.5 vs 42.3± 3.1; 2mg/kg: 36.2±1.8) and RVH (1 mg/kg: 0.47±0.06 vs 0.4+0.08; 2mg/Kg: 0.34±0.01) was observed with both the doses of tranylcypromine; however, 2mg/Kg dose showed better effects. Bleo‐induced lung fibrosis was also reduced by drug treatment as evaluated by picro‐sirius red staining. Collectively, our findings reveal that inhibition of LSD1 by tranylcypromine protects against bleo‐induced cardiopulmonary damage.

Effects of combined angiotensin II receptor antagonism and neprilysin inhibition in experimental pulmonary hypertension and right ventricular failure

BackgroundCombined angiotensin II receptor antagonism and neprilysin inhibition by LCZ696 reduces morbidity and mortality in heart failure patients and works by reducing RAAS activity and increasing cGMP levels. This study aims to evaluate the effects of LCZ696 in rats with pulmonary hypertension and right ventricular (RV) failure. MethodsPulmonary hypertension was induced in rats (n = 34) by combined exposure to the vascular endothelial growth factor-receptor antagonist SU5416 and hypoxia (SuHx). To distinguish pulmonary vascular from cardiac effects, isolated RV failure was induced by pulmonary trunk banding (PTB) in another group of rats (n = 40). In both models, the development of RV dysfunction was verified before randomization to treatment with LCZ696 (60 mg/kg/day) or vehicle for five weeks. ResultsIn the SuHx rats, LCZ696 treatment reduced the increase in RV pressure and the development of RV hypertrophy and RV dilatation compared with vehicle treatment. LCZ696 also reduced wall thickness of the smaller pulmonary arteries. In the PTB rats, LCZ696 treatment did not have any effects on RV hypertrophy or function. ConclusionsCombined angiotensin II receptor antagonism and neprilysin inhibition reduced RV systolic pressure, hypertrophy, and dilatation in rats with pulmonary hypertension. These effects seem secondary to pulmonary vascular changes, including reduced pulmonary vascular remodeling, as similar effects were not seen in rats with isolated RV failure. LCZ696 may have a therapeutic potential in the treatment of pulmonary hypertension.

Altered proteasome function in right ventricular hypertrophy

In patients with pulmonary hypertension, right ventricular hypertrophy (RVH) is a detrimental condition that ultimately results in right heart failure and death. The ubiquitin proteasome system has been identified as a major protein degradation system to regulate cardiac remodelling in the left heart. Its role in right heart hypertrophy, however, is still ambiguous. RVH was induced in mice by pulmonary artery banding (PAB). Both, expression and activity of the proteasome was found to be up-regulated in the hypertrophied right ventricle (RV) compared to healthy controls. Catalytic inhibition of the proteasome by the two proteasome inhibitors Bortezomib (BTZ) and ONX-0912 partially improved RVH both in preventive and therapeutic applications. Native gel analysis revealed that specifically the 26S proteasome complexes were activated in experimental RVH. Increased assembly of 26S proteasomes was accompanied by elevated expression of Rpn6, a rate-limiting subunit of 26S proteasome assembly, in hypertrophied cardiomyocytes of the right heart. Intriguingly, patients with RVH also showed increased expression of Rpn6 in hypertrophied cardiomyocytes of the RV as identified by immunohistochemical staining. Our data demonstrate that alterations in expression and activity of proteasomal subunits play a critical role in the development of RVH. Moreover, this study provides an improved understanding on the selective activation of the 26S proteasome in RVH that might be driven by the rate-limiting subunit Rpn6. In RVH, Rpn6 therefore represents a more specific target to interfere with proteasome function than the commonly used catalytic proteasome inhibitors.

Proteinase-activated receptor 1 antagonism ameliorates experimental pulmonary hypertension.

Pulmonary hypertension (PH) is characterized by progressive increases in pulmonary vascular resistance (PVR). Thrombotic lesions are common pathological findings. The pulmonary artery has a unique property regarding the vasoconstrictive response to thrombin, which is mediated by proteinase-activated receptor 1 (PAR1). We aim to elucidate the role of PAR1 in the development and progression of PH. A rat model of monocrotaline-induced PH and a mouse model of hypoxia (Hx)-induced PH were used to investigate the effects of atopaxar (a PAR1 antagonist) and PAR1 knockout on haemodynamic parameters, right ventricular hypertrophy (RVH), vascular remodelling and survival. In perfused lung preparations, the pressor response to PAR1 agonist was significantly augmented in monocrotaline-induced PH. Both the preventive and therapeutic administration of atopaxar significantly inhibited the increase in PVR and the development of RVH and prolonged survival. A real-time PCR revealed that the level of PAR1 mRNA in the pulmonary artery was significantly higher than that in any of the systemic arteries examined in control rats, and the level was significantly up-regulated in monocrotaline-induced PH. PAR1 gene knockout significantly attenuated the haemodynamic and histological findings in the mouse model of Hx-induced PH. The specific expression of PAR1 in the pulmonary artery and its up-regulation were suggested to play a critical role in the development and progression of experimental PH in murine models. PAR1 is a potential therapeutic target for the treatment of PH.

Maprotiline Prevents Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats.

Pulmonary arterial hypertension (PAH) is a progressive disease caused by increased pulmonary artery pressure and pulmonary vascular resistance, eventually leading to right heart failure until death. Soluble guanylate cyclase (sGC) has been regarded as an attractive drug target in treating PAH. In this study, we discovered that maprotiline, a tetracyclic antidepressant, bound to the full-length recombinant sGC with a high affinity (KD = 0.307 μM). Further study demonstrated that maprotiline concentration-dependently inhibited the proliferation of hypoxia-induced human pulmonary artery smooth muscle cells. Moreover, in a monocrotaline (MCT) rat model of PAH, maprotiline (ip, 10 mg/kg once daily) reduced pulmonary hypertension, inhibited the development of right ventricular hypertrophy and pathological changes of the pulmonary vascular remodeling. Taken together, our studies showed that maprotiline may contribute to attenuate disease progression of pulmonary hypertension.

Loss of KCNK3 is a hallmark of RV hypertrophy/dysfunction associated with pulmonary hypertension.

Mutations in the KCNK3 gene, which encodes for an outward-rectifier K+ channel, have been identified in patients suffering from pulmonary arterial hypertension (PAH), and constitute the first described channelopathy in PAH. In human PAH and experimental pulmonary hypertension (PH), we demonstrated that KCNK3 expression and function are severely reduced in pulmonary vascular cells, promoting PH-like phenotype at the morphologic and haemodynamic levels. Since KCNK3 channel is also expressed in both the human and rodent heart, we aimed to elucidate the pathophysiological role of KCNK3 channel in right ventricular (RV) hypertrophy (RVH) related to PH. Using whole-cell Patch-clamp technique, we demonstrated that KCNK3 is predominantly expressed in adult rat RV cardiomyocytes compared to the left ventricle cardiomyocytes and participates in the repolarizing phase of the RV action potential. We revealed a reduction in KCNK3 function prior to development of RVH and the rise of pulmonary vascular resistance. KCNK3 function is severely reduced in RV cardiomyocytes during the development of RVH in several rat models of PH (exposure to monocrotaline, chronic hypoxia, and Sugen/hypoxia) and chronic RV pressure overload (pulmonary artery banding). In experimental PH, we revealed a reduction in KCNK3 function before any rise in pulmonary vascular resistance and the development of RVH. KCNK3 mRNA level is also reduced in human RV tissues from PAH patients compared to non-PAH patients. In line with these findings, chronic inhibition of KCNK3 in rats with the specific inhibitor (A293) induces RV hypertrophy which is associated with the re-expression of foetal genes, RV fibrosis, RV inflammation, and subsequent loss of RV performance as assessed by echocardiography. Our data indicate that loss of KCNK3 function and expression is a hallmark of the RV hypertrophy/dysfunction associated with PH.

Abstract 399: End-stage Heart Failure Causes Severe Lung Fibrosis and Dysfunction

Chronic heart failure (CHF) causes trouble breathing in patients. We recently demonstrated that systolic pressure overload by transverse aortic constriction (TAC) causes severe left ventricular (LV) failure that is associated with massive lung fibrosis and lung vascular remodeling, and right ventricular (RV) dysfunction in mice. Here, we further studied the effect of CHF on lung structure and function in mice, and the effect of CHF on lung fibrosis in patients. We demonstrated that chronic TAC resulted in decrease of LV ejection fraction, and increases LV weight, lung weight, and RV weight, as well as their ratios to bodyweight. Interestingly, the development of LV failure is associated with a significant lung dysfunction as evidenced by a ~2-fold increase of lung resistance and a ~50% dramatic decrease of lung compliance in vivo . Lung compliance was also significantly reduced ~50% in lung isolated from CHF mice, indicating the decrease of lung compliance is due to the structure change of lung. The reduced lung compliance in CHF mice is significantly correlated with the decrease of LV ejection fraction, the increase of lung weight, and RV hypertrophy, suggesting the reduced lung compliance might contribute to the development of RV hypertrophy and failure. Histochemical analyses further demonstrated that CHF causes massive lung vascular, perivascular and interstitial fibrosis, as well as increase of lung myofibroblast proliferation. By using the chimeric mice created by transplantation of Bone Marrow Derived Cells (BMDCs) from GFP mice into wild type mice, we demonstrated that BMDCs contribute to the increased lung myofibroblasts and lung fibrosis. However, BMDCs don’t differentiate into lung smooth muscles cells in CHF mice. Moreover, we demonstrated that inhibition of lung inflammation by a cytokine therapy protocol is effective in attenuating TAC-induced lung fibrosis. Finally, we demonstrated that end-stage CHF causes increase of lung fibrosis in patients, and the increased lung fibrosis is associated with RV hypertrophy and dysfunction in patients. Together, our study demonstrated that end-stage CHF causes lung fibrosis and lung dysfunction, and inhibition of inflammation is effective in attenuating heart failure induced lung fibrosis.

Endothelial hyperpermeability in severe pulmonary arterial hypertension: role of store-operated calcium entry.

Here, we tested the hypothesis that animals with severe pulmonary arterial hypertension (PAH) display increased sensitivity to vascular permeability induced by activation of store-operated calcium entry. To test this hypothesis, wild-type and transient receptor potential channel 4 (TRPC4) knockout Fischer 344 rats were given a single injection of Semaxanib (SU5416; 20 mg/kg) followed by 3 wk of exposure to hypoxia (10% oxygen) and a return to normoxia (21% oxygen) for an additional 2-3 wk. This Semaxanib/hypoxia/normoxia (i.e., SU5416/hypoxia/normoxia) treatment caused PAH, as evidenced by development of right ventricular hypertrophy, pulmonary artery medial hypertrophy, and occlusive lesions within precapillary arterioles. Pulmonary artery pressure was increased fivefold in Semaxanib/hypoxia/normoxia-treated animals compared with untreated, Semaxanib-treated, and hypoxia-treated controls, determined by isolated perfused lung studies. Thapsigargin induced a dose-dependent increase in permeability that was dependent on TRPC4 in the normotensive perfused lung. This increase in permeability was accentuated in PAH lungs but not in Semaxanib- or hypoxia-treated lungs. Fluid accumulated in large perivascular cuffs, and although alveolar fluid accumulation was not seen in histological sections, Evans blue dye conjugated to albumin was present in bronchoalveolar lavage fluid of hypertensive but not normotensive lungs. Thus PAH is accompanied by a TRPC4-dependent increase in the sensitivity to edemagenic agents that activate store-operated calcium entry.

Diminazene, an ACE2 Activator Modulates Gut Microbiota and Provides Protection Against Pulmonary Hypertension

We have previously demonstrated that Diminazene aceturate (DIZE), an ACE2 activator attenuates pulmonary hypertension (PH). It is becoming clearer that disruption of the gut microbiome leads to metabolic and cardiovascular diseases. However, role of the gut microbiome in PH has not yet been studied. We hypothesized that PH is associated with microbial dysbiosis, and that treatment with DIZE restores the gut microbiome to provide cardiopulmonary protection. PH was induced in male Sprague Dawley rats by a single subcutaneous injection of monocrotaline (MCT, 50mg/Kg). A subset of MCT animals was treated daily with DIZE (15mg/kg, ip) for 4‐weeks, after which echocardiographic and hemodynamic measurements were performed, and fecal samples collected for microbiome analyses. MCT rats showed marked increase in right ventricular systolic pressure (RVSP; Control: 32+3 mmHg; MCT: 88+2 mmHg), along with the development of right ventricular hypertrophy (RVH; Control: 0.26+0.005; MCT: 0.61+0.01), which was associated with significant changes in the composition of the gut microbiota, and decreased levels of butyrate, a beneficial microbial metabolite. However, DIZE treatment restored the gut microbiome and increased butyrate levels to attenuate PH (RVSP; MCT+DIZE: 55+2mmHg) and associated cardiac hypertrophy (RVH; MCT+DIZE: 0.38+0.005). Collectively, our results demonstrate that PH is associated with microbial dysbiosis and that DIZE treatment modulates the gut microbiome to provide cardiopulmonary protection.

The hypoxia-induced microRNA-130a controls pulmonary smooth muscle cell proliferation by directly targeting CDKN1A

Excessive proliferation of human pulmonary artery smooth muscle cells (HPASMC) is one of the major factors that trigger vascular remodeling in hypoxia-induced pulmonary hypertension. Several studies have implicated that hypoxia inhibits the tumor suppressor p21 (CDKN1A). However, the precise mechanism is unknown.The mouse model of hypoxia-induced PH and in vitro experiments were used to assess the impact of microRNAs (miRNAs) on the expression of CDKN1A. In these experiments, the miRNA family miR-130 was identified to regulate the expression of CDKN1A. Transfection of HPASMC with miR-130 decreased the expression of CDKN1A and, in turn, significantly increased smooth muscle proliferation. Conversely, inhibition of miR-130 by anti-miRs and seed blockers increased the expression of CDKN1A. Reporter gene analysis proved a direct miR-130–CDKN1A target interaction. Exposure of HPASMC to hypoxia was found to induce the expression of miR-130 with concomitant decrease of CDKN1A. These findings were confirmed in the mouse model of hypoxia-induced pulmonary hypertension showing that the use of seed blockers against miR-130 restored the expression of CDKN1A.These data suggest that miRNA family miR-130 plays an important role in the repression of CDKN1A by hypoxia. miR-130 enhances hypoxia-induced smooth muscle proliferation and might be involved in the development of right ventricular hypertrophy and vascular remodeling in pulmonary hypertension.

Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension.

Pulmonary vascular remodeling, mainly attributable to enhanced pulmonary arterial smooth muscle cell proliferation and migration, is a major cause for elevated pulmonary vascular resistance and pulmonary arterial pressure in patients with pulmonary hypertension. The signaling cascade through Akt, comprised of three isoforms (Akt1-3) with distinct but overlapping functions, is involved in regulating cell proliferation and migration. This study aims to investigate whether the Akt/mammalian target of rapamycin (mTOR) pathway, and particularly which Akt isoform, contributes to the development and progression of pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension (HPH). Compared with the wild-type littermates, Akt1(-/-) mice were protected against the development and progression of chronic HPH, whereas Akt2(-/-) mice did not demonstrate any significant protection against the development of HPH. Furthermore, pulmonary vascular remodeling was significantly attenuated in the Akt1(-/-) mice, with no significant effect noted in the Akt2(-/-) mice after chronic exposure to normobaric hypoxia (10% O2). Overexpression of the upstream repressor of Akt signaling, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), and conditional and inducible knockout of mTOR in smooth muscle cells were also shown to attenuate the rise in right ventricular systolic pressure and the development of right ventricular hypertrophy. In conclusion, Akt isoforms appear to have a unique function within the pulmonary vasculature, with the Akt1 isoform having a dominant role in pulmonary vascular remodeling associated with HPH. The PTEN/Akt1/mTOR signaling pathway will continue to be a critical area of study in the pathogenesis of pulmonary hypertension, and specific Akt isoforms may help specify therapeutic targets for the treatment of pulmonary hypertension.