Mechanism of Abnormal Activation of JAK-STAT Signaling Pathway in High-Altitude Polycythemia-Related Heart Failure And Specific Inhibitor Intervention
Journal: Journal of Clinical Medicine Research DOI: 10.32629/jcmr.v6i3.4422
Abstract
To elucidate the mechanism of abnormal activation of the JAK-STAT signaling pathway in heart failure associated with high-altitude erythrocytosis (HAPC) and to evaluate the therapeutic potential of targeted inhibitors, this study integrated preclinical models, clinical cohort studies, and molecular biology experiments. We dissect how hypoxic stress, inflammatory cascades, and neuroendocrine dysregulation converge to drive JAK-STAT overactivation, promote erythropoiesis, myocardial remodeling, and then cause heart dysfunction. Key findings highlight the JAK2-STAT5 axis as a critical mediator of excessive erythropoiesis in HAPC, while JAK1-STAT3/STAT1 signaling contributes to myocardial hypertrophy and fibrosis. We also assess the efficacy of JAK kinase inhibitors and STAT-targeted peptides in mitigating these pathological processes, emphasizing their potential to reverse hemorheological abnormalities and protect cardiac structure-function. This synthesis provides a framework for translating JAK-STAT pathway inhibition into clinical practice for HAPC-related heart failure, with recommendations for optimizing inhibitor specificity and minimizing off-target effects.
Keywords
cardiology; signaling pathway; heart failure; high altitude disease
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[3] Semenza GL. Hyoxia-inducible factor 1: master regulator of O2 homeostasis. Current Opinion in Genetics & Development, 2000, 10(1): 50-55.
[4] Cai Y, Zhang Y, Wang Y, et al. Oxidative stress-induced JAK/STAT activation in cardiac myocytes: role of mitochondria and NADPH oxidase. American Journal of Physiology - Heart and Circulatory Physiology, 2008, 295(2): H736-H743.
[5] Heinrich PC, Behrmann I, Haan S, et al. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochemical Journal, 2003, 374(Pt 1): 1-20.
[6] Winslow RL, McMullen JR, Molkentin JD. Molecular mechanisms of cardiac hypertrophy. Annual Review of Physiology, 2003, 65: 523-553.
[7] Frey N, Olson EN. Cardiac hypertrophy: the good, the bad, and the ugly. Annual Review of Physiology, 2003, 65: 45-79.
[8] Sadoshima J, Izumo S. Signaling pathways for cardiac hypertrophy and failure. Annual Review of Physiology, 1997, 59: 551-571.
[9] Zhang X, Li X, Wang Y, et al. Effects of tofacitinib on high-altitude polycythemia-related heart failure in a rat model. Journal of Cardiovascular Pharmacology, 2023, 81(3): 225-233.
[10] Song X, Chen Y, Li Y, et al. Peptide-based inhibitors of STAT proteins: design, synthesis, and biological evaluation. Bioorganic & Medicinal Chemistry Letters, 2022, 32(18): 128447.
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