Key result
Buthutin A attenuates AngII-induced cardiac hypertrophy and apoptosis via NHE1 inhibition.
Why the study?
NHE1 inhibitors are considered promising for cardiovascular diseases, prompting evaluation of the novel NHE1 inhibitor Buthutin A against angiotensin II-induced injury in vitro and in vivo.
p-value: p=<0.05
Buthutin A, a novel NHE1 inhibitor, protects against AngII-induced cardiac injury and oxidative stress in vitro and in vivo, suggesting potential as a therapeutic agent for cardiovascular diseases.
Buthutin A effects remain preclinical; leaves open whether NHE1 inhibition benefits patients with cardiac hypertrophy.
Objective: Na+/H+-exchanger 1 (NHE1) inhibitors are considered promising drugs for cardiovascular diseases. Buthutin A (Buth A) is a novel NHE1 inhibitor that was reported by our team recently. In this research, we explored the protective effect of Buth A against angiotensin II (AngII)-induced injury invitro and in vivo. Methods: H9c2 cells and human umbilical vein endothelial cells (HUVECs) were divided into eight groups to investigate whether NHE1, cytosolic calcium ([Ca2+]c), conventional protein kinase C (cPKC), and PKCβ are associated with the protective effect of Buth A invitro. Meanwhile, myocardial hypertrophy was induced by AngII in adult male C57BL/6 mice to verify the protective effect of Buth A invivo. Results: Buth A significantly increased cell viability in AngII-treated H9c2 and HUVEC cells, as well as the superoxide dismutase (SOD) activity of AngII-treated H9c2 cells. Moreover, Buth A reduced the lactate dehydrogenase (LDH) and reactive oxygen species (ROS) levels, number of TUNEL-positive cells, and Bax/Bcl-2 protein expression ratio in AngII-treated H9c2 and HUVEC cells. It also significantly decreased the malondialdehyde (MDA) levels, cell size, and mitochondrial membrane potential in H9c2 cells, all of which were attenuated by the NHE1 activator (LiCl). We further found that the calcium chelator (BAPTA-AM), Na+/Ca2+-exchanger (NCX) inhibitor (SN6), cPKC inhibitor (Go6976), and PKCβ inhibitor (LY317615) had no effect on the protective effect of Buth A in HUVECs, including the inhibition of oxidative stress and apoptosis. Further results indicated that Buth A alleviated oxidative stress and apoptosis caused by myocardial hypertrophy via NHE1 inhibition in AngII-induced mice. Conclusions: Buth A reduced oxidative stress-induced apoptosis and exerted protective effects against AngII-induced cardiac injury invivo and invitro via NHE1 inhibition, which might be associated with [Ca2+]c and PKCβ activities.
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Shao et al. (2026) studied Angiotensin II-induced myocardial hypertrophy and oxidative stress (n=40). Buthutin A vs. Angiotensin II alone (Model group) or Saline (Control) was evaluated on Cardiac hypertrophy, oxidative stress, and apoptosis markers (e.g., heart weight/body weight ratio, ROS levels, TUNEL-positive cells) (p=<0.05). Buthutin A significantly reduced oxidative stress-induced apoptosis and attenuated cardiac hypertrophy and dysfunction in AngII-treated mice and cells via NHE1 inhibition.
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