Related Experiment Video
Updated: May 22, 2025
Mechanism of Kemeng Fang's Inhibition of Podocyte Apoptosis in Rats with Membranous Nephropathy through the PI3K/AKT Signaling Pathway
Published on: August 23, 2024
KAT7 contributes to ponatinib-induced hypertension by promoting endothelial senescence and inflammatory responses
Liang-Liang Tang1, Xin-Yu Xu1, Mei Zhang2,3
1Department of Pharmacy and Cardiology, Harbin Medical University (HMU) Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Heilongjiang Key Laboratory for Metabolic Disorders and Cancer related Cardiovascular Diseases.
Background And Purpose:
Ponatinib, a tyrosine kinase inhibitor (TKI) leads to hypertension; however, the mechanisms remain elusive. We aimed to investigate whether lysine acetyltransferase 7 (KAT7), a key regulator of cellular senescence that is closely associated with cardiovascular diseases, involves in ponatinib-induced hypertension.
Methods And Results:
After administering ponatinib to Sprague-Dawley (SD) rats for 8 days, we measured blood pressure, vasodilation, and endothelial function using tail-cuff plethysmography, isometric myography, and the Total NO Assay kit, respectively. The results indicated that ponatinib increased blood pressure, impaired endothelium-dependent relaxation (EDR), and caused injury to endothelial cells in SD rats. Furthermore, PCR and Western blot experiments demonstrated an upregulation of KAT7 expression in rat mesenteric artery endothelial cells (MAECs) following ponatinib treatment. To further study the role of KAT7 in ponatinib-induced hypertension, we divided the SD rats into four groups: control, ponatinib, WM-3835 (a KAT7 inhibitor), and ponatinib plus WM-3835. Notably, WM-3835 administration significantly improved ponatinib-induced hypertension and EDR dysfunction in SD rats. Mechanistically, over-expression of KAT7 (OE-KAT7) in MAECs led to cellular senescence and inflammation, phenomena that were also observed in the mesenteric arteries of ponatinib-treated rats and in MAECs exposed to ponatinib. However, WM-3835 mitigated these detrimental effects in both in vivo and in vitro experiments. Additionally, both OE-KAT7 and ponatinib treatment induced H3K14 acetylation (H3K14ac), with OE-KAT7 also elevating the recruitment of the H3K14ac to the p21 promoter. Moreover, BAY 11-7085, a nuclear factor (NF)-κB inhibitor, potently alleviated the accumulation of IL-6 and IL-8, as well as endothelial cell senescence induced by ponatinib and KAT7 overexpression.
Conclusion:
Our data indicate that ponatinib-induced elevation of KAT7 led to endothelial cells senescence and inflammatory responses through H3K14 acetylation and NF-κB signaling pathway, subsequently caused vasotoxicity and hypertension.
Insights
Ponatinib-induced hypertension is linked to increased KAT7, causing endothelial cell senescence and inflammation via H3K14 acetylation and NF-κB signaling. Inhibiting KAT7 with WM-3835 improved hypertension and endothelial dysfunction.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Pharmacology
Background:
- Ponatinib, a tyrosine kinase inhibitor (TKI), is known to cause hypertension through mechanisms that are not fully understood.
- Lysine acetyltransferase 7 (KAT7) is a regulator of cellular senescence implicated in cardiovascular diseases.
Purpose of the Study:
- To investigate the role of KAT7 in ponatinib-induced hypertension.
- To elucidate the molecular mechanisms linking ponatinib treatment to hypertension.
Main Methods:
- Administration of ponatinib and a KAT7 inhibitor (WM-3835) to Sprague-Dawley rats.
- Measurement of blood pressure, vasodilation, and endothelial function.
- Analysis of KAT7 expression, H3K14 acetylation, and NF-κB signaling in endothelial cells and rat mesenteric arteries.
Main Results:
- Ponatinib treatment increased blood pressure, impaired endothelial-dependent relaxation, and induced endothelial cell injury in rats.
- KAT7 expression was upregulated in rat mesenteric artery endothelial cells (MAECs) after ponatinib treatment.
- Inhibition of KAT7 with WM-3835 ameliorated ponatinib-induced hypertension and endothelial dysfunction.
- Overexpression of KAT7 in MAECs induced cellular senescence and inflammation, mimicking effects of ponatinib.
- Ponatinib and KAT7 overexpression promoted H3K14 acetylation and activated NF-κB signaling, leading to increased IL-6 and IL-8, which were mitigated by WM-3835 and BAY 11-7085.
Conclusions:
- Ponatinib-induced hypertension is mediated by elevated KAT7, leading to endothelial cell senescence and inflammation.
- The mechanism involves H3K14 acetylation and activation of the NF-κB signaling pathway.
- Targeting KAT7 may offer a therapeutic strategy for managing ponatinib-induced hypertension.
Related Concept Videos
01:26Treatment for Pulmonary Arterial Hypertension: Receptor Tyrosine Kinase Inhibitors and Calcium Channel Blockers
TKIs, such as imatinib (Gleevec), are particularly effective in tackling the growth and mitogenic factors that become upregulated in PAH patients. These factors contribute to the...
01:18Treatment for Pulmonary Arterial Hypertension: Endothelin Receptor Antagonists
ETs are synthesized through a complex sequence of enzymatic steps, primarily involving an enzyme referred to as endothelin-converting enzyme...
01:22PI3K/mTOR/AKT Signaling Pathway
02:26NF-κB-dependent Signaling Pathway
NF-κB-dependent Signaling Mechanism
The...
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
01:24Regulation of Angiogenesis and Blood Supply