Targeting Molecular Mechanism of Vascular Smooth Muscle Senescence Induced by Angiotensin II, A Potential Therapy via Senolytics and Senomorphics

Abstract

Cardiovascular disease (CVD) is a prevalent issue in the global aging population. Premature vascular aging such as elevated arterial stiffness appears to be a major risk factor for CVD. Vascular smooth muscle cells (VSMCs) are one of the essential parts of arterial pathology and prone to stress-induced senescence. The pervasiveness of senescent VSMCs in the vasculature increases with age and can be further expedited by various stressing events such as oxidative stress, mitochondria dysfunction, endoplasmic reticulum stress, and chronic inflammation. Angiotensin II (AngII) can induce many of these responses in VSMCs and is thus considered a key regulator of VSMC senescence associated with CVD. Understanding the precise mechanisms and consequences of senescent cell accumulation may uncover a new generation of therapies including senolytic and senomorphic compounds against CVD. Accordingly, in this review article, we discuss potential molecular mechanisms of VSMC senescence such as those induced by AngII and the therapeutic manipulations of senescence to control age-related CVD and associated conditions such as by senolytic.

EZH2 Regulates ANXA6 Expression via H3K27me3 and Is Involved in Angiotensin II-Induced Vascular Smooth Muscle Cell Senescence

“…It is known that ROS are the mechanism of Ang II-induced VSMC senescence [ 1 , 20 , 21 ], and ROS induces cell cycle arrest [ 22 ]. Therefore, we confirmed the influence of ANXA6 on Ang II-induced ROS.…”

From Cultured Vascular Cells to Vessels: The Cellular and Molecular Basis of Vascular Dysfunction in Space

“…However, also radiations and increased amounts of stress and inflammatory mediators, reactive oxygen species (ROS), insulin and angiotensin II –as described in astronauts (see above)- should be taken into account. As an example, high angiotensin II triggers oxidative stress, mitochondrial dysfunction, and promotes vSMC senescence ( Okuno et al, 2020 ), beyond sensitizing the cells to the detrimental effects of catecholamines. Ionizing radiations change vSMC phenotype ( Heckenkamp et al, 2004 ) and increase the sensitivity of their myofilaments to Ca 2+ through the activation of protein kinase C ( Soloviev et al, 2005 ).…”

The mechanisms of vascular aging

“…Ang II originating from Ang I by ACE is involved in the vascular remodeling process that acts via angiotensin II type 1 receptor (AT1R) and type 2 (AT2R) 14,15 . Ang II is involved in the inflammatory process, which increases the activation of inflammatory factors by activating nuclear transcription factor‐kappa B (NF‐κB) through AT1R and AT2R during vascular aging 16,17 . When activated, NF‐κB translocates to the nucleus and then upregulates the expression of inflammatory cytokines, resulting in vascular injury and atherosclerosis 18 .…”

“…14,15 Ang II is involved in the inflammatory process, which increases the activation of inflammatory factors by activating nuclear transcription factor-kappa B (NF-κB) through AT1R and AT2R during vascular aging. 16,17 When activated, NF-κB translocates to the nucleus and then upregulates the expression of inflammatory cytokines, resulting in vascular injury and atherosclerosis. 18 Growing research shows that inhibiting vascular inflammation is the principal factor for the prevention and treatment of aging-related vascular diseases.…”