Agonist-induced Piezo1 activation promote mitochondrial-dependent apoptosis in vascular smooth muscle cells

Abstract

Objective Mechanical damage plays an essential role in the progression of atherosclerosis. Piezo1 is a new mechanically sensitive ion channel. The present study investigated the vascular smooth muscle cells (VSMCs) apoptosis induced by Piezo1 activation and explored its underlying mechanism. Methods We evaluated cell viability and apoptosis rate with cell counting kit-8 (CCK-8) and Annexin V-FITC/PI flow cytometry assay, respectively. And then Western blot was performed to measure the relative protein. Reactive oxygen species (ROS) and intracellular Ca2+ were assessed via fluorescence microscope, and the mitochondrial transmembrane potential was monitored by JC-10 staining. Results Our in vitro study revealed that mice in the ApoE-/- group compared with control mice showed higher Piezo1 expression(P < 0.05). Besides, Yoda1, a Piezo1 agonist, triggered Ca2+ overload, mitochondrial damage, accumulation of ROS, and VSMCs apoptosis in a dose-depend manner. Furthermore, BAPT-AM (an intracellular Ca2+ chelator) and NAC (an antioxidant) suppressed the mitochondrial damage and attenuated the VSMCs apoptosis. Conclusion Our study suggested that Piezo1 induced VSMCs apoptosis because of Ca2+ overload, excessive ROS generation, and mitochondrial dysfunction, which indicated that Piezo1 has potential value in treating vascular diseases.

Hypertensive Pressure Mechanosensing Alone Triggers Lipid Droplet Accumulation and Transdifferentiation of Vascular Smooth Muscle Cells to Foam Cells

“…[46] VSMC Piezo1 was further linked to increased contraction and proliferation [17,47] and apoptosis. [48] Additionally, Piezo1 was upregulated in abdominal aortic aneurysms downstream of netrin-1. [49] Although the Piezo channels are generally targeted to the plasma membrane, [50,51] where they are localized in a curvature dependent way, [52] localization to diverse intracellular membranous organelles, including sarcoplasmic and endoplasmic reticulum, mitochondria, Golgi has been reported before.…”

Piezo1-mediated microtubule destabilisation promotes extracellular matrix rigidity induced smooth muscle cell hypertrophy

“…Specifically, we identify piezo1 as a driver of ECM rigidity induced VSMC hypertrophy. VSMC piezo1 expression is upregulated in mouse models of atherosclerosis and abdominal aortic aneurysms, with dysregulation of VSMC mechanosensation shown to drive these disease states (Qian et al, 2022;Yin et al, 2022). Furthermore, reduced aortic compliance is observed in both atherosclerosis and abdominal aortic aneurysms (Glasser et al, 1997;Mitchell et al, 2010;Lacolley et al, 2017).…”

“…The above data shows that VSMC hypertrophy on rigid substrates is mediated by SAC activation. Piezo1 is a SAC known to be involved in atherosclerosis and abdominal aortic aneurysm mediated VSMC dysfunction (Qian et al, 2022;Yin et al, 2022). Whether piezo1 is involved in VSMC hypertrophy remains unknown.…”

“…This stimulates VSMC contraction as a result of calcium ion influx. These SACs are also reported to contribute to VSMC dysfunction, with piezo1 implicated in atherosclerosis and abdominal aortic aneurysm induced vascular remodelling (Qian et al, 2022;Yin et al, 2022). Whether SACs, including piezo1, are involved in VSMC hypertrophy and the mechanisms by which they drive VSMC dysfunction remain unknown.…”

Aging-associated Decline in Vascular Smooth Muscle Cell Mechanosensation is Mediated by Piezo1 Channel

“…VSMC mechanosensation depends on the swift opening of Piezo1, a tension-gated ion channel that allows the influx of calcium (Ca 2+ ) ions upon activation to regulate the vascular development, blood pressure, and hypertension-dependent arterial remodeling [18][19][20][21]. Recent studies identified Piezo1 as the culprit for VSMC maladaptive mechanosensation in aortic aneurysm, a lethal vascular disease that affects almost exclusively the aged population [22].…”