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

Tang, Haiyang; Chen, Jiwang; Fraidenburg, Dustin R.; Song, Shanshan; Sysol, Justin R.; Drennan, Abigail; Offermanns, Stefan; Ye, Richard D.; Bonini, Marcelo G.; Minshall, Richard D.; Garcia, Joe G.N.; Machado, Roberto F.; Makino, Ayako; Yuan, Jason X.‐J.

doi:10.1152/ajplung.00242.2014

Cited by 80 publications

(101 citation statements)

References 78 publications

(93 reference statements)

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“…Indeed, we detected significantly higher Yap/Taz protein levels, activity ( components to the pulmonary hypertension (PH) network (27) (see Figure E6) from which the AKT set was ranked as a most probable candidate. A proliferative/antiapoptotic role of mTORAkt and Notch3 intracellular domain in PAH PAVSMCs had been reported by us and others (5,28,29), and we confirmed activation of HIF1 and Wnt/b-catenin using respective activation assays (see Figure E7). Supporting the bioinformatic predictions, inactivation of LATS1 in nondiseased human PAVSMCs significantly up-regulated mTOR-Akt, as evidenced by increase in P-S473 Akt, mTORC2-specific P-T2481 mTOR, and mTORC1-specific P-S6 (5,14,(30)(31)(32), and led to accumulation of b-catenin, Notch3 intracellular domain, and HIF1a, whereas "restoration" of P-T1079 LATS1 or suppression of Yap in PAH PAVSMCs by LATS1 T1079D or VP had the opposite effect ( Figure 3; see Figure E8).…”

Section: Hippo/lats1 Inactivation Promotes Human Pah Pavsmc Proliferasupporting

confidence: 89%

HIPPO–Integrin-linked Kinase Cross-Talk Controls Self-Sustaining Proliferation and Survival in Pulmonary Hypertension

Kudryashova

Goncharov

Pena

et al. 2016

Am J Respir Crit Care Med

105

183

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Rationale: Enhanced proliferation and impaired apoptosis of pulmonary arterial vascular smooth muscle cells (PAVSMCs) are key pathophysiologic components of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH).Objectives: To determine the role and therapeutic relevance of HIPPO signaling in PAVSMC proliferation/apoptosis imbalance in PAH.Methods: Primary distal PAVSMCs, lung tissue sections from unused donor (control) and idiopathic PAH lungs, and rat and mouse models of SU5416/hypoxia-induced pulmonary hypertension (PH) were used. Immunohistochemical, immunocytochemical, and immunoblot analyses and transfection, infection, DNA synthesis, apoptosis, migration, cell count, and protein activity assays were performed in this study. Measurements and Main Results:Immunohistochemical and immunoblot analyses demonstrated that the HIPPO central component large tumor suppressor 1 (LATS1) is inactivated in small remodeled pulmonary arteries (PAs) and distal PAVSMCs in idiopathic PAH. Molecular-and pharmacology-based analyses revealed that LATS1 inactivation and consequent up-regulation of its reciprocal effector Yes-associated protein (Yap) were required for activation of mammalian target of rapamycin (mTOR)-Akt, accumulation of HIF1a, Notch3 intracellular domain and b-catenin, deficiency of proapoptotic Bim, increased proliferation, and survival of human PAH PAVSMCs. LATS1 inactivation and up-regulation of Yap increased production and secretion of fibronectin that upregulated integrin-linked kinase 1 (ILK1). ILK1 supported LATS1 inactivation, and its inhibition reactivated LATS1, down-regulated Yap, suppressed proliferation, and promoted apoptosis in PAH, but not control PAVSMCs. PAVSM in small remodeled PAs from rats and mice with SU5416/hypoxia-induced PH showed downregulation of LATS1 and overexpression of ILK1. Treatment of mice with selective ILK inhibitor Cpd22 at Days 22-35 of SU5416/hypoxia exposure restored LATS1 signaling and reduced established pulmonary vascular remodeling and PH.Conclusions: These data report inactivation of HIPPO/LATS1, self-supported via Yap-fibronectin-ILK1 signaling loop, as a novel mechanism of self-sustaining proliferation and apoptosis resistance of PAVSMCs in PAH and suggest a new potential target for therapeutic intervention.

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Section: Hippo/lats1 Inactivation Promotes Human Pah Pavsmc Proliferasupporting

confidence: 89%

HIPPO–Integrin-linked Kinase Cross-Talk Controls Self-Sustaining Proliferation and Survival in Pulmonary Hypertension

Kudryashova

Goncharov

Pena

et al. 2016

Am J Respir Crit Care Med

105

183

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“…Resveratrol inhibited hypoxia-induced arginase activity as well as proliferation in human PASMCs (39) and in vivo resveratrol treatment attenuated the development of hypoxia-induced RVH in rats. The effect of resveratrol upon arginase II was mediated via inhibition of the PI3K-Akt signaling pathway, findings consistent with other recent reports demonstrating a role for Akt signaling in PASMC proliferation in response to hypoxia (233). The Akt family contains three isoforms, and the use of mice with deficiency for Akt1 or Akt2 revealed that loss of Akt1 prevented hypoxia-induced proliferation in vitro and development of hypoxia-induced PH.…”

Section: Pathways and Targetssupporting

confidence: 90%

Update on novel targets and potential treatment avenues in pulmonary hypertension

Huetsch

Suresh

Bernier

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pulmonary hypertension (PH) is a condition marked by a combination of constriction and remodeling within the pulmonary vasculature. It remains a disease without a cure, as current treatments were developed with a focus on vasodilatory properties but do not reverse the remodeling component. Numerous recent advances have been made in the understanding of cellular processes that drive pathologic remodeling in each layer of the vessel wall as well as the accompanying maladaptive changes in the right ventricle. In particular, the past few years have yielded much improved insight into the pathways that contribute to altered metabolism, mitochondrial function, and reactive oxygen species signaling and how these pathways promote the proproliferative, promigratory, and antiapoptotic phenotype of the vasculature during PH. Additionally, there have been significant advances in numerous other pathways linked to PH pathogenesis, such as sex hormones and perivascular inflammation. Novel insights into cellular pathology have suggested new avenues for the development of both biomarkers and therapies that will hopefully bring us closer to the elusive goal: a therapy leading to reversal of disease.

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“…Thus, we could also speculate that miR-223 downregulation can also lead to increased KLF5 expression observed in PAH (8). Moreover, downstream miR-223 targets IGF-1R and HSP90␤ seem to act on proliferation through the phosphatidylinositol 3-kinase, Akt, and mammalian target of rapamycin (PI3K/Akt/ mTOR) pathway (13,18) known to play a role in PAH pathophysiology (10,26,36).…”

Section: Discussionmentioning

confidence: 99%

miR-223 reverses experimental pulmonary arterial hypertension

Meloche

Guen

Potus

et al. 2015

American Journal of Physiology-Cell Physiology

107

111

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nary arterial hypertension (PAH) is a devastating disease affecting lung vasculature. The pulmonary arteries become occluded due to increased proliferation and suppressed apoptosis of the pulmonary artery smooth muscle cells (PASMCs) within the vascular wall. It was recently shown that DNA damage could trigger this phenotype by upregulating poly(ADP-ribose)polymerase 1 (PARP-1) expression, although the exact mechanism remains unclear. In silico analyses and studies in cancer demonstrated that microRNA miR-223 targets PARP-1. We thus hypothesized that miR-223 downregulation triggers PARP-1 overexpression, as well as the proliferation/apoptosis imbalance observed in PAH. We provide evidence that miR-223 is downregulated in human PAH lungs, distal PAs, and isolated PASMCs. Furthermore, using a gain and loss of function approach, we showed that increased hypoxia-inducible factor 1␣, which is observed in PAH, triggers this decrease in miR-223 expression and subsequent overexpression of PARP-1 allowing PAH-PASMC proliferation and resistance to apoptosis. Finally, we demonstrated that restoring the expression of miR-223 in lungs of rats with monocrotaline-induced PAH reversed established PAH and provided beneficial effects on vascular remodeling, pulmonary resistance, right ventricle hypertrophy, and survival. We provide evidence that miR-223 downregulation in PAH plays an important role in numerous pathways implicated in the disease and restoring its expression is able to reverse PAH. miR-223; pulmonary hypertension; PARP-1; HIF-1␣; DNA damage PULMONARY ARTERIAL HYPERTENSION (PAH) is a serious condition characterized by obstruction of the precapillary pulmonary arterioles (PA) due to excessive vasoconstriction, inflammation, and imbalance between cells' proliferation and apoptosis within the arterial wall. This remodeling and obstruction of the PAs leads to increases in pulmonary vascular resistance, right ventricular (RV) failure, and death of patients. Despite recent therapeutic advances, most patients exhibit persistently poor exercise capacity and quality of life, with a 3-yr survival rate of 65% (12).Growing evidence underlines the importance of DNA damage in PAH etiology (9,19,23). Indeed, the sustained inflammation, RAGE expression (21), and metabolic stress (30) observed in PAH result in DNA damage-dependent activation of poly(ADP-ribose)polymerase 1 (PARP-1) in PA smooth muscle cells (PASMCs) of PAH patients (23). We recently showed that PARP-1 overexpression was responsible for enhanced PAH-PASMC proliferation and suppressed apoptosis (23). Nevertheless, the mechanisms that regulate this overexpression in PAH remain elusive.In cancer, PARP-1 expression is regulated by microRNA-223 (miR-223), a microRNA involved in DNA damage response (34). According to TargetScan 6.2, PARP-1 is in fact a predicted target of miR-223. Moreover, downregulation of miR-223 has been shown to mediate mechanical stretch-stimulated proliferation of vascular smooth muscle cells (33). Interestingly, Wang et al. (38) reported that miR-...

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

Cited by 80 publications

References 78 publications

HIPPO–Integrin-linked Kinase Cross-Talk Controls Self-Sustaining Proliferation and Survival in Pulmonary Hypertension

HIPPO–Integrin-linked Kinase Cross-Talk Controls Self-Sustaining Proliferation and Survival in Pulmonary Hypertension

Update on novel targets and potential treatment avenues in pulmonary hypertension

miR-223 reverses experimental pulmonary arterial hypertension

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