Effect of SKF‑96365 on cardiomyocyte hypertrophy induced by angiotensin II

Abstract

angiotensin ii (ang ii) is an important bioactive peptide in the renin-angiotensin system, and it can contribute to cell proliferation and cardiac hypertrophy. dysfunctions in transient receptor potential canonical (TrPc) channels are involved in many types of cardiovascular diseases. The aim of the present study was to investigate the role of the TrPc channel inhibitor SKF-96365 in cardiomyocyte hypertrophy induced by ang ii and the potential mechanisms of SKF-96365. H9c2 cells were treated with different concentrations of ang ii. The expression levels of cardiomyocyte hypertrophy markers and TrPc channel-related proteins were also determined. The morphology and surface area of the H9c2 cells, the expression of hypertrophic markers and TrPc channel-related proteins and the [ 3 H] leucine incorporation rate were detected in the ang ii-treated H9c2 cells following treatment with the TrPc channel inhibitor SKF-96365. The intracellular ca 2+ concentration was tested by flow cytometry. The present results suggested that the surface area of H9c2 cells treated with ang ii was significantly increased compared with untreated H9c2 cells. The fluorescence intensity of α-actinin, the expression of hypertrophic markers and TrPc-related proteins, the [ 3 H] leucine incorporation rate and the intracellular ca 2+ concentration were all markedly increased in the ang ii-treated H9c2 cells but decreased following SKF-96365 treatment. The present results suggested that ang ii induced cardiomyocyte hypertrophy in H9c2 cells and that the TrPc pathway may be involved in this process. Therefore, SKF-96365 can inhibit cardiomyocyte hypertrophy induced by ang ii by suppressing the TrPc pathway. The present results indicated that TrPc may be a therapeutic target for the development of novel drugs to treat cardiac hypertrophy.

An Insight on Multicentric Signaling of Angiotensin II in Cardiovascular system: A Recent Update

“…Levels of Brn-3b mRNA and related proteins are increased in Ang II treated mouse hearts and foetal heart-derived H9c2 cells or primary cultures of neonatal rat ventricular myocytes with varied hypertrophic alterations. Alternate signaling pathways involved in activation of Brn-3b promoter include p42/p44 MAPK/ERK1/2 or calcineurin pathways ( Mele et al, 2019 ; Cheng et al, 2020 ). Cardiac fibrosis is induced by the pro (renin) receptor, which could be more worsened by the involvement PRR-ERK1/2-NOX4 pathway and ROS during the development of alcoholic cardiomyopathy ( Cao et al, 2019 ).…”

Transient Receptor Potential Canonical (TRPC) Channels: Then and Now

“…In the heart, the phenomenon of hypertrophy results from increased cardiomyocyte size, which is secondary to pressure or mechanical overload. Several studies provided evidence that TRPC channels may contribute to the development of cardiac hypertrophy [ 129 , 130 , 131 , 132 , 133 ]. Hearts from hypertrophic patients had higher TRPC1 expression [ 134 ], and the cardiomyocytes from hypertrophic mouse models showed upregulated TRPC1/TRPC4 function [ 135 ].…”

“…These inhibitors blocked pathological hypertrophic signaling in adult cardiac myocytes [ 130 ]. SK&F-96365, an unspecific inhibitor of receptor-operated, Cav, and TRPC channels, also attenuated cardiomyocyte hypertrophy induced by Ang II [ 133 ]. Interestingly, it was demonstrated that the protection conferred by TRPC3 deletion is not only due to the reduction of Ca 2+ influx mediated by TRPC3, but also through the modulation of Ca V 1.2 expression, which is downregulated in TRPC3 KO mice and leads to reduced response in phenylephrine-induced cardiac hypertrophy [ 131 ].…”

Therapeutic effects of SKF-96365 on murine allergic rhinitis induced by OVA

“…10 1-[2-(4-methoxyphenyl)-2-[3-(4-methoxyphenyl) propoxy]ethyl-1H-imidazole (SKF-96365) is a small molecule compound acting as a non-selective inhibitor of TRP channels, SOCE and voltagegated Ca 2+ channels, and SKF-96365 has been proved to suppress cellular Ca 2+ influx via inhibiting these Ca 2+ channels. [11][12][13] There is ample evidence that SKF-96365 is widely used to study the function of TRPC channels. [12][13][14][15][16][17] Previous reports indicate that SKF 96365 could suppress cardiomyocyte hypertrophy, and inhibit spontaneous nociception and pain hypersensitivity induced by melittin via inactivating TRPC channels and Ca 2+ influx.…”

“… 12 – 17 Previous reports indicate that SKF 96365 could suppress cardiomyocyte hypertrophy, and inhibit spontaneous nociception and pain hypersensitivity induced by melittin via inactivating TRPC channels and Ca 2+ influx. 12 , 18 In cultured NECs, TRPC6, STIM1, Orai1, Ca 2+ MFI levels, and inflammatory mediators were upregulated by lipopolysaccharide (LPS) and 1-oleoyl-2-acetyl-glycerol (OAG, diacylglycerol (DAG) analog, TRPC6 activator), but were inhibited by SKF-96365. 10 In addition, 2-aminoethoxydiphenyl borate (2-APB) is a chemical which could inhibit SOCE and TRP channels, 19 , 20 and one previous report has indicated that 2-APB administration intranasally could reduce numbers of sneezing, nasal rubbing, and eosinophils in murine AR.…”