Abstract 221: Integral Role of Akt-Serum Response Factor-Myocardin Signaling in Myofibroblast Differentiation with Implications in Pulmonary Arterial Hypertension

Objectives Myofibroblast (MF) differentiation is marked by the de novo expression of smooth muscle alpha-actin (αSMA) stress fibers, a function critical for tissue repair both physiologically and pathophysiologically. However, the role of Akt in regulating MFs with implications in pulmonary arterial hypertension (PAH) and fibrosis, and the effect of pharmacological inhibition of Akt pathway on PAH and fibrosis remains poorly defined. Methods We used NIH 3T3 fibroblasts and primary human lung fibroblasts (HLFs) in the current study. Cells were treated with TGFβ, the profibrotic cytokine and the role of Akt, SRF and myocardin in αSMA expression, MF differentiation and collagen gel contraction was studied with the use of various constructs encoding expression of specific genes. Results Here, we show that Akt mediates MF differentiation as evident by a 5-fold increase in αSMA expression and assembly in mouse embryonic fibroblasts (NIH 3T3) over-expressing active Akt1 (myr-Akt). As for the molecular mechanisms governing MFs, we found that αSMA expression was mediated by Akt, independent of mTOR; noteworthy, fibronectin expression, an ECM protein, is Akt-mTOR dependent. Inhibiting Akt activation utilizing triciribine blunted αSMA and its transcriptional activators, myocardin and SRF, inhibiting MF differentiation in NIH 3T3, myr-Akt-NIH 3T3, and human lung fibroblasts. Furthermore, blocking Akt reversed MF differentiation as evident by a blunted gel contraction primed with TGFβ. Conclusions In conclusion, our study clearly demonstrates the crucial role of Akt in mediating TGFβ-induced MF differentiation. We show a previously uncharacterized link between Akt and TGFβ-induced αSMA synthesis through myocardin and SRF, independent of mTOR, in MFs. These data constitute evidence of novel signaling cascade and targeting Akt pathway might be beneficial for the treatment of PAH and fibrosis.

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Metabolomics Based Mechanism Exploration of Pulmonary Arterial Hypertension pathogenesis: Novel Lessons from Explanted Lungs

10.21203/rs.3.rs-820723/v1 ◽

2021 ◽

Author(s):

Jingjing Ding ◽

Chunyan Chu ◽

Zhengsheng Mao ◽

Jiawen Yang ◽

Jie Wang ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Metabolic Pathways ◽

Molecular Mechanisms ◽

Akt Pathway ◽

Analysis Model ◽

Chi Square ◽

Exact Probability ◽

Lung Cancer Patients ◽

Pulmonary Arterial

Abstract Background: Metabolic pathways have been shown to participate in the pathogenesis of pulmonary arterial hypertension (PAH). We investigated the metabolic profile shifts to reveal molecular mechanisms underlying PAH. Methods: Explanted human lung tissues from 18 PAH patients were collected. The lung tissues far from the tumor from 16 lung cancer patients were taken as controls. Lung tissues were analyzed by LC-MS/MS based non-target metabolomics method. Pathway analysis was performed with KEGG database and MetaboAnalyst 5.0. Statistical analysis including partial least squares discriminant analysis (PLS-DA), Student’s t-test, Pearson’s correlation, Chi-square test and Fisher’s exact probability test were used. COX survival analysis model was applied to evaluate the predictive value of metabolites on prognosis. Protein expression levels were detected by Western blotting in human PAH lung tissues, rat monocrotaline-PAH lungs and hypoxia exposed human pulmonary artery smooth muscle cells (HPASMCs) to study the molecular mechanisms.Results: Significant differences in metabolites and metabolic pathways were identified among PAH subgroups and control tissues. Spermine levels were positively correlated with the patients' cardiac outputs (COs). Levels of (2e)-2,5-dichloro-4-oxo-2-hexenedioic acid were positively correlated with the patient's serum creatinine (Scr) levels. Patients with higher levels of thymine had a better prognosis. Moreover, 7 differential metabolites were associated with AKT pathway. AKT pathway inactivation was confirmed in human and rat PAH lungs and hypoxia exposed HPASMCs.Conclusions: Our findings provide the first metabolomics evidence for PAH pathogenesis by human lungs and may contribute to the improvement of therapeutic strategy.

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Navigating the Road to Transplant in Pulmonary Arterial Hypertension: A Road Less Taken

Advances in Pulmonary Hypertension ◽

10.21693/1933-088x.15.1.12 ◽

2016 ◽

Vol 15 (1) ◽

pp. 12-13

Author(s):

Adaani E. Frost ◽

Harrison W. Farber

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Lung Transplantation ◽

Small Cell ◽

Small Cell Lung ◽

Donor Organ ◽

The Road ◽

Lung Allocation Score ◽

Pulmonary Arterial

Dramatic advances in therapy for pulmonary arterial hypertension (PAH) in the last 20 years have improved survival from a median of 2.5 years in the pretreatment era to 7.5 years currently. However, impressive as that may seem, it is important to note that a median survival of 7.5 years is equivalent to that of surgically resected non-small cell lung cancer, thus underscoring the importance of lung transplantation as a treatment option in patients with PAH. In this edition of Advances, Edelman has reviewed the pathway to transplantation for patients with PAH, detailing the recommendations for timing of referral, listing for lung transplantation, the role of the lung allocation score in allocating a donor organ, and the outcome of lung transplantation.

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An Expanding Role of Biomarkers in Pulmonary Arterial Hypertension

Current Pharmaceutical Biotechnology ◽

10.2174/1389201018666170615082510 ◽

2017 ◽

Vol 18 (6) ◽

Cited By ~ 3

Author(s):

Mustafa Yildiz ◽

Alparslan Sahin ◽

Michael Behnes ◽

İbrahim Akin

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Pulmonary Arterial

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Research Progress on Pulmonary Arterial Hypertension and the Role of the Angiotensin Converting Enzyme 2-Angiotensin-(1–7)-Mas Axis in Pulmonary Arterial Hypertension

Cardiovascular Drugs and Therapy ◽

10.1007/s10557-020-07114-6 ◽

2021 ◽

Author(s):

Feng Zhang ◽

Aidong Chen ◽

Yan Pan ◽

Xingxing Wang ◽

Yu Xu ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Angiotensin Converting Enzyme ◽

Arterial Hypertension ◽

Research Progress ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Pulmonary Arterial

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Sex differences in pulmonary arterial hypertension: role of infection and autoimmunity in the pathogenesis of disease

Biology of Sex Differences ◽

10.1186/s13293-018-0176-8 ◽

2018 ◽

Vol 9 (1) ◽

Cited By ~ 20

Author(s):

Kyle A. Batton ◽

Christopher O. Austin ◽

Katelyn A. Bruno ◽

Charles D. Burger ◽

Brian P. Shapiro ◽

...

Keyword(s):

Sex Differences ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Pulmonary Arterial

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Cardiac baroreflex dysfunction in patients with pulmonary arterial hypertension at rest and during orthostatic stress: Role of the peripheral chemoreflex

Journal of Applied Physiology ◽

10.1152/japplphysiol.00152.2021 ◽

2021 ◽

Author(s):

Marcelle Paula-Ribeiro ◽

Indyanara C. Ribeiro ◽

Liliane C. Aranda ◽

Talita M. Silva ◽

Camila M. Costa ◽

...

Keyword(s):

Blood Pressure ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Early Stage ◽

Pressure Fluctuations ◽

Sit To Stand ◽

Peak Aerobic Capacity ◽

Pulmonary Arterial ◽

Peripheral Chemoreflex

The baroreflex integrity in early-stage pulmonary arterial hypertension (PAH) remains uninvestigated. A potential baroreflex impairment could be functionally relevant and possibly mediated by enhanced peripheral chemoreflex activity. Thus, we investigated 1) the cardiac baroreflex in non-hypoxemic PAH; 2) the association between baroreflex indexes and peak aerobic capacity (i.e., V̇O2peak); and 3) the peripheral chemoreflex contribution to the cardiac baroreflex. Nineteen patients and 13 age- and sex-matched healthy adults (HA) randomly inhaled either 100% O2 (peripheral chemoreceptors inhibition) or 21% O2 (control session), while at rest and during a repeated sit-to-stand maneuver. Beat-by-beat analysis of R-R intervals and systolic blood pressure provided indexes of cardiac baroreflex sensitivity (cBRS) and effectiveness (cBEI). The PAH group had lower cBEIALL at rest (mean ± SD: PAH = 0.5 ± 0.2 vs HA = 0.7 ± 0.1 a.u., P = 0.02) and lower cBRSALL (PAH = 6.8 ± 7.0 vs HA = 9.7 ± 5.0 ms mmHg-1, P < 0.01) and cBEIALL (PAH = 0.4 ± 0.2 vs HA= 0.6 ± 0.1 a.u., P < 0.01) during the sit-to-stand maneuver versus the HA group. The cBEI during the sit-to-stand maneuver was independently correlated to V̇O2peak (partial r = 0.45, P < 0.01). Hyperoxia increased cBRS and cBEI similarly in both groups at rest and during the sit-to-stand maneuver. Therefore, cardiac baroreflex dysfunction was observed under spontaneous and, most notably, provoked blood pressure fluctuations in non-hypoxemic PAH, was not influenced by the peripheral chemoreflex, and was associated with lower V̇O2peak suggesting it could be functionally relevant.

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