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Role and Mechanism of Notch1 in Cardiomyocyte Response to Mechanical Stretch in Hypertensive Cardiac Hypertrophy and NSAID Intervention

Author(s)

Xin Zhang1, XiaoMei Fan1, YanJun Chen1, ZhongHua Liu2,*

Affiliation(s)

1Basic Medical School, Inner Mongolia Medical University, Hohhot, Inner Mongolia, China 2The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia, China *Corresponding Author

Abstract

This study investigates the role and mechanisms of Notch1 in cardiomyocytes under mechanical stretch in the context of hypertensive cardiac hypertrophy and NSAID intervention. Using adult Sprague-Dawley rats, cardiomyocytes were isolated and cultured to establish a mechanical stretch model. Various intensities of mechanical stretch were applied to observe the expression and distribution of Notch1 and related signaling proteins (e. g., Hes1, KLF2, FABP4). Techniques such as Western blot, ELISA, immunofluorescence, electron microscopy, and RT-PCR were employed to comprehensively assess cardiomyocyte responses. Experimental groups included controls, mechanical stretch, siRNA, 50 μM DAPT, and Notch1 overexpression, with data collected at multiple time points. Results indicated that mechanical stretch significantly activated the Notch signaling pathway, promoting cardiomyocyte hypertrophy. In contrast, siRNA-mediated Notch1 silencing, DAPT inhibition of the Notch pathway, or NSAID treatment effectively suppressed stretch-induced hypertrophy. Notch1 plays a crucial role in cell-cell interactions, alignment, and proliferation, possibly regulating cardiomyocyte structure and function. NSAIDs, by modulating the Notch pathway, markedly inhibit cardiac hypertrophy, suggesting a novel therapeutic approach for hypertensive cardiac hypertrophy.

Keywords

Notch1; Mechanical Stretch; Cardiac Hypertrophy; NSAID; Signaling Pathway

References

[1] Jiang Ruiyuan. Research on the Effects of NSAIDs on Cardiac Structure and Function in Rats with Pressure Overload Hypertrophy Mediated by the Notch1 Signaling Pathway [J]. [2021-05-01]. [2] Imbimbo, B. P. Therapeutic Potential of Gamma-Secretase Inhibitors and Modulators [J]. Current Topics in Medicinal Chemistry, 2008, 8(1). [3] Weggen, S., Eriksen, J. L., Das, P., et al. A Subset of NSAIDs Lower Amyloidogenic Aβ42 Independently of Cyclooxygenase Activity [J]. Nature, 2001, 414(6860). [4] Giardina, G. A., Imbimbo, et al. Gamma-Secretase Inhibitors and Modulators for the Treatment of Alzheimer's Disease: Disappointments and Hopes [J]. Current Topics in Medicinal Chemistry, 2011. [5] Shen Chunduo, Sun Kai, Zhang Weili, et al. Advances in Genetics of Ischemic Stroke [J]. Chinese Journal of Molecular Cardiology, 2006, 6(4):5. [6] Zhang Lifang, Yang Xiaosu, Wang Yufen, et al. Clinical and Genetic Studies of a Family with Autosomal Dominant Cerebral Arteriopathy Accompanied by Subcortical Infarcts and Leukoaraiosis [J]. Chinese Journal of Medical Genetics, 2009, 26(2):4. [7] Liu Yu, Yang Hui, Li Huihua. Advances in the Study of the Correlation between Notch and NF-κB Signaling Pathways and Myocardial Remodeling [J]. Chinese Journal of Arteriosclerosis, 2011, 19(3):2. [8] Crump C J, Johnson D S, Li Y M. Development and mechanism of γ-secretase modulators for Alzheimer's disease. [J]. Biochemistry, 2013, 52(19):3197-3216. DOI:10.1021/bi400377p. [9] Imbimbo B P. Therapeutic Potential of γ -Secretase Inhibitors and Modulators [J]. Current Topics, 2008. [10] Lanz, T. A. Lack of Specific Amyloid-(1-42) Suppression by Nonsteroidal Anti-Inflammatory Drugs in Young, Plaque-Free Tg2576 Mice and in Guinea Pig Neuronal Cultures [J]. Journal of Pharmacology & Experimental Therapeutics, 2004, 312(1):399-406. [11] Sagi S A, Lessard C B, Winden K D, et al. Substrate sequence influences γ-secretase modulator activity, role of the transmembrane domain of the amyloid precursor protein. [J]. Journal of Biological Chemistry, 2011, 286. [12] Mistry S. A CELLULAR THERAPY FOR OCULAR DEGENERATION:11/446462[P]. US20060280729[2024-11-26]. [13] Yasuko Takahashi, Ikuo Hayashi, Yusuke. Molecular Basis of Cell and Developmental Biology: Sulindac sulfide is a non-competitive γ -secretase inhibitor that preferentially reduces A β42 generation [J]. [2024-11-26]. [14] Zhang H, Ye Y, Bai Z, et al. the COX-2 selective inhibitor-independent COX-2 effect on colon carcinoma cells is associated with the Delta1/Notch1 pathway. [J]. Digestive Diseases and Sciences, 2008, 53(8):2195-2203. [15] Mackey A L, Rasmussen L K, Kadi F, et al. Activation of satellite cells and the regeneration of human skeletal muscle are expedited by ingestion of nonsteroidal anti-inflammatory medication [J]. Faseb Journal Official Publication of the Federation of American Societies for Experimental Biology, 2016, 30(6):2266-2281. [16] Abigail L, Mackey, Lotte K, et al. Activation of satellite cells and the regeneration of human skeletal muscle are expedited by ingestion of nonsteroidal anti-inflammatory medication. [J]. FASEB journal: official publication of the Federation of American Societies for Experimental Biology, 2016. [17] Amy Tran‐Guzman, Khan A, Culty M. Differential roles of cyclooxygenase enzymes in the regulation of murine juvenile undifferentiated spermatogonia [J]. Andrology, 2024, 12(4). [18] Sperry B P, Cheney C W, Conger A, et al. Cooled Radiofrequency Ablation of a Large Sciatic Neuroma at the Infrapiriformis Foramen for Recalcitrant Phantom Limb Pain in a Below-Knee Amputee [J]. Pain Medicine, 2020, 22(10):1-4.