Compensatory activation of PI3K/AKT signaling and apoptosis-associated protein expression in pulmonary hypertension‑induced right ventricular dysfunction

Q: What are the key findings of this study?

Hypobaric hypoxia-induced pulmonary hypertension significantly enriched RV PI3K/AKT signaling (NES 2.14, P<0.001) alongside increased Bax, decreased Bcl-2, and RV fibrosis in mice.

Q: What is the clinical evidence from this study?

Population: Pulmonary hypertension-induced right ventricular dysfunction (n=16). Intervention: Hypobaric hypoxia (in vivo) / LY294002 PI3K inhibitor + Angiotensin II (in vitro) vs. Normoxic control (21% O2) / Angiotensin II alone. Primary outcome: PI3K/AKT signaling pathway enrichment in right ventricular tissue (Gene Set Enrichment Analysis) (NES 2.14, p=<0.001).

Q: What does this research mean for the field?

Hypobaric hypoxia-induced pulmonary hypertension enriches right ventricular PI3K/AKT signaling as a compensatory, anti-apoptotic response alongside increased Bax/Bcl-2 ratio and myocardial fibrosis. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

Investigate the role of PI3K/AKT signaling and apoptosis-associated protein expression during right ventricular remodeling in pulmonary hypertension.

Han Zhang; Qixu Zhao; Jiashu Sun; Yusong Deng; Guofeng Xing; Wei-Ran Duan; Gang Li; Qiang Wang

doi:10.3892/etm.2026.13342

October 23, 2026Experimental and Therapeutic MedicineOpen Access

Compensatory activation of PI3K/AKT signaling and apoptosis-associated protein expression in pulmonary hypertension‑induced right ventricular dysfunction

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Key result

Hypobaric hypoxia activates RV PI3K/AKT signaling and drives pro-apoptotic remodeling in pulmonary hypertension.

NES 2.14
P<0.001
n=16

Why the study?

Right ventricular dysfunction is the principal determinant of mortality in patients with pulmonary hypertension, but the role of the PI3K/AKT pathway in pulmonary hypertension-induced right ventricular remodeling remained poorly defined.

Does hypobaric hypoxia-induced pulmonary hypertension alter PI3K/AKT signaling and apoptosis-associated protein expression in murine right ventricular remodeling, and does PI3K inhibition with LY294002 exacerbate angiotensin II-induced pro-apoptotic signaling in H9C2 cardiomyocytes?

Key Points

Investigate the role of PI3K/AKT signaling and apoptosis-associated protein expression during right ventricular remodeling in pulmonary hypertension.
Established a pulmonary hypertension model in C57BL/6J mice subjected to 28 days of hypobaric hypoxia, assessing cardiac dimensions and function using echocardiography (n=8 per group).
Characterized right ventricular fibrosis, cardiomyocyte proliferation (Ki-67), and apoptosis markers (Bax and Bcl-2) using histology, immunofluorescence, RT-qPCR, western blotting (n=6 per group), and RNA sequencing.
Treated cultured H9C2 cardiomyocytes with angiotensin II in the presence or absence of the selective PI3K inhibitor LY294002 to evaluate apoptosis-associated protein regulation.
Transcriptomic analysis of right ventricular tissue from pulmonary hypertension mice demonstrated significant enrichment of the PI3K/AKT signaling pathway (normalized enrichment score, 2.14; P<0.001; KEGG FDR<0.01).
Pulmonary hypertension mice exhibited right ventricular fibrosis, significant upregulation of Bax, downregulation of Bcl-2 (P<0.05), and a small increase in Ki-67-positive cardiomyocytes to ~0.4% (P<0.05).
In angiotensin II-treated H9C2 cardiomyocytes, blocking PI3K/AKT signaling with LY294002 further upregulated Bax and downregulated Bcl-2 expression at both mRNA and protein levels.

Structured PICO

Does hypobaric hypoxia-induced pulmonary hypertension alter PI3K/AKT signaling and apoptosis-associated protein expression in murine right ventricular remodeling, and does PI3K inhibition with LY294002 exacerbate angiotensin II-induced pro-apoptotic signaling in H9C2 cardiomyocytes?

P

Population

16 male C57BL/6J mice (8 weeks old, 20-25 g) randomized to hypobaric hypoxia-induced pulmonary hypertension or normoxic control for 28 days, alongside in vitro H9C2 cardiomyocyte experiments.

I

Intervention

In vivo: continuous exposure to a hypobaric chamber simulating 5,500 m altitude (10% O2) for 28 days to induce PH. In vitro: H9C2 cells treated with 1 µM angiotensin II (Ang II) for 24 h, with or without 30 min pretreatment with 10 µM LY294002 (a selective PI3K inhibitor)

C

Comparator

In vivo: normoxic control mice (n=8) housed under normal atmospheric conditions with 21% O2 for 28 days. In vitro: untreated control H9C2 cells and cells treated with 1 µM Ang II alone without LY294002

O

Outcome

Right ventricular (RV) remodeling, transcriptomic signaling pathway enrichment (specifically PI3K/AKT via RNA sequencing), and apoptosis-associated protein/mRNA expression (Bax and Bcl-2) at 28 days in vivo and 24 hours in vitrosurrogate

Main Result

Effect estimate: NES 2.14

p-value: p=<0.001

In a murine model of pulmonary hypertension, right ventricular dysfunction and fibrosis are accompanied by transcriptomic enrichment of the PI3K/AKT pathway, which acts as an endogenous but insufficient compensatory survival mechanism against cardiomyocyte apoptosis.

Limitations

Conducted exclusively in male mice, limiting generalizability to females
Focused only on apoptosis without exploring other forms of programmed cell death such as pyroptosis or ferroptosis
Downstream effectors and crosstalk with other signaling cascades were not investigated in detail
Findings were derived only from animal and cell models and lack validation in human pulmonary hypertension samples
Ki-67 staining indicates cell-cycle activity but cannot confirm completion of the cell cycle or cytokinesis
Ki-67 staining alone cannot determine whether cells progressed through the cell cycle or completed cytokinesis, and Ki-67-positive cardiomyocytes accounted for only ~0.4% of examined cells.

Implication

Preclinical findings should not yet change practice; leaves open whether targeting PI3K/AKT signaling can mitigate right ventricular remodeling in human pulmonary hypertension.

Abstract

Pulmonary hypertension (PH) is a progressive cardiopulmonary disorder marked by increased pulmonary vascular resistance and poor prognosis.Right ventricular (RV) dysfunction is the principal determinant of mortality in patients with PH; however, the role of the PI3K/AKT pathway in PH-induced RV remodeling remains poorly defined.The present study generated a hypobaric hypoxia-induced PH model in C57BL/6J mice.Echocardiography, histology, reverse transcription-quantitative PCR, western blotting and immunofluorescence staining were employed to assess RV structure, apoptosis-associated protein expression and fibrosis, while RNA sequencing was used to identify enriched signaling pathways.In parallel, H9C2 cardiomyocytes were treated with angiotensin II (Ang II) with or without the PI3K inhibitor LY294002 to evaluate apoptosis-associated protein expression changes.PH model mice developed RV dysfunction characterized by increased Bax and decreased Bcl-2 expression, accompanied by fibrosis.Transcriptomic analysis revealed significant enrichment of the PI3K/AKT pathway in RV tissues from PH model mice compared with control mice.Pharmacological inhibition of PI3K/AKT signaling with LY294002 further upregulated Bax and downregulated Bcl-2 in Ang II-treated H9C2 cells.In conclusion, PI3K/AKT pathway enrichment may represent a compensatory but insufficient response during PH-induced RV remodeling, and its precise modulation may offer a potential therapeutic strategy for PH-associated RV failure.

Discussion

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Cite This Study

Zhang et al. (2026) studied Pulmonary hypertension-induced right ventricular dysfunction (n=16). Hypobaric hypoxia (in vivo) / LY294002 PI3K inhibitor + Angiotensin II (in vitro) vs. Normoxic control (21% O2) / Angiotensin II alone was evaluated on PI3K/AKT signaling pathway enrichment in right ventricular tissue (Gene Set Enrichment Analysis) (NES 2.14, p=<0.001). Hypobaric hypoxia-induced pulmonary hypertension significantly enriched RV PI3K/AKT signaling (NES 2.14, P<0.001) alongside increased Bax, decreased Bcl-2, and RV fibrosis in mice.

synapsesocial.com/papers/6ae28e94cbadf70daf6c43b1 https://doi.org/10.3892/etm.2026.13342

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Compensatory activation of PI3K/AKT signaling and apoptosis-associated protein expression in pulmonary hypertension‑induced right ventricular dysfunction

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Compensatory activation of PI3K/AKT signaling and apoptosis-associated protein expression in pulmonary hypertension‑induced right ventricular dysfunction

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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