Hypertension is a highly complex, intricate condition affecting millions of individuals across the globe. Nearly half of adults in the United States are diagnosed with hypertension, with incident rates projected to rise over the next decade. Hypertension is a precursor to many cardiovascular diseases including atherosclerosis, stroke, myocardial infarction, heart failure, and peripheral artery disease. The Sestrin (SESN) family of proteins is comprised of three members Sesn1, Sens2, and Sesn3, and is expressed by three coding genes: SESN1, SESN2, and SESN3
1. Background and Function
The Sestrin (SESN) family of proteins is comprised of three members Sesn1, Sens2, and Sesn3, and is expressed by three coding genes: SESN1, SESN2, and SESN3 
. These proteins are characterized as stress-inducible-metabolic regulators and are upregulated during high-stress conditions such as DNA damage and oxidative stress 
. Of the three members of the family, Sesn2 is the main protein responsible for responding to increases in oxidative stress 
. Sesn2 also serves a variety of beneficial functions. Sesn2 can activate adenosine monophosphate-activated protein kinase (AMPK), thus inhibiting the mammalian target of rapamycin (mTOR) 
. Further, Sesn2 can coordinate various antioxidant pathways, act directly as an antioxidant enzyme, and produce anti-inflammatory effects 
. These unique properties can combat the etiology of hypertension, making Sesn2 an excellent target in the development of therapeutic treatment plans for hypertension.
Sesn2 is a fully alpha helical globular monomeric protein with a molecular weight of approximately 55 kDa 
. Three main substructures are of note with Sesn2: an N-terminal domain (SesnA) and a C-terminal domain (SesnB), which are connected by a linker region (SesnC) 
. SesnA, a small area of residues in the N-terminal domain, is the location of Sesn2′s antioxidant enzyme activity, acting as an alkyl hydroperoxide reductase 
. Sesn2 can interact with leucine, which structurally occurs near the SesnB region of residues Asp 406 and Asp 407 
. The effective interaction with leucine is of utmost importance, as leucine is necessary to further induce AMPK activation, reducing the activity of mTORC1, and is also involved in many biological processes of Sesn2 functioning 
. Continuing, researchers will further discuss the axiomatic relationships of various signaling pathways of Sesn2, including nuclear factor erythroid 2-related factor 2 (Nrf2), AMPK/mTORC, and Ang II in relation to hypertension. With insight into the regulatory properties of Sesn2 in these various signaling pathways, researchers will then discuss how Sesn2 can be utilized as a treatment option for hypertension.
3. Sesn2 and Nrf2
Nuclear factor erythroid 2 (Nrf2) is a transcription factor involved in the expression of antioxidant proteins 
. Nrf2 is found in the cytoplasm during normal physiological conditions bound by Keap-1 and undergoes normal proteasomal degradation to maintain homeostatic levels 
. Under oxidative stress conditions, Nrf2 travels to the nucleus where it binds to the antioxidant response element (ARE) region of antioxidant genes 
. This gene region promotes the production of several antioxidant proteins including Sesn2 (Figure 1
. Nrf2 also contributes to the expression of the anti-hypertensive enzyme heme-oxygenase 1 (HO-1). Increased expression of HO-1 degrades heme, producing carbon monoxide, bilirubin, and iron 
. The carbon monoxide created is a known vasodilator. Proper vasodilatory effects can aid in the regulation of vascular tone, a hallmark characteristic misregulated in hypertension.
Nrf2/Sesn2/Nox axis and hypertension (created with BioRender.com
, accessed on 11 May 2023).
Nrf2 and Sesn2 interact in a positive feedback loop manner 
As mentioned, Nrf2 activation induces the production of Sesn2. After Sens2 is produced, it can act as a scaffold protein, promoting the degradation of Keap-1, thus leading to more Nrf2 activation and further promoting the production of various antioxidants 
. As previously mentioned, NOX isoforms contribute to the development of hypertension via the overproduction of ROS. The Nrf2/Sesn2 axis is highly affiliated with changes in the expression of the NOX family isoforms 
. Proper management of overactive NOX is essential to mitigate the ROS produced during the development of hypertension. NOX2 elevation is directly associated with increases in blood pressure. Studies show that with Nrf2 deficiency, NOX2 upregulation is observed, linking the potential of the Nrf2/Sesn2 axis to hypertension 
. Also, as previously described, NOX4 has vasculo-protective effects. NOX4 upregulation is associated with increases in Nrf2 
. Based on these findings, Nrf2 agonists such as curcumin and sulforaphane have been the focus of current research. Due to the complexity and the specific nature of Nrf2 activation, an effective agonist has yet to be developed to target hypertension. The Sesn2/Nrf2/NOX family axis is a high-profile target in the development of a treatment option for hypertension and warrants further investigation.
4. Sesn2 and Angiotensin II
The peptide, Ang II, is a major component in the renin–angiotensin system (RAS) 
. The RAS is responsible for the regulation of key factors seen in hypertension, such as electrolyte balance, the regulation of blood volume, and vascular resistance 
. Overactivation/misregulation of the RAS, including Ang II, can result in a multitude of diseases including hypertension. In hypertension, overactive Ang II can activate NADPH oxidase and produce increased amounts of ROS 
. The ROS produced due to the overactivation of Ang II produces pro-inflammatory effects. These effects include alterations in vascular permeability, cytokine production, misregulation of tissue repair, and dysfunction of leukocyte extravasation 
. Proper management of the overactive Ang II exhibited in hypertension by Sesn2 can lead to a decrease in the ROS produced by NADPH oxidase (Figure 2
). Targeting Ang II could therefore reduce the major pro-inflammatory progression of hypertension and produce a reduction in pathophysiology. Sesn2 is well known to interact with Ang II. Specifically, Ang II can increase the proliferation of cardiac fibroblasts and increase the production of collagen 
. Multiple studies have demonstrated Sesn2′s effects on Ang II in ameliorating these effects 
. Studies involving human umbilical vein cells show Sesn2 decreasing Ang II-induced ROS production 
. Also, silencing Sens2 resulted in worsened cell viability and increased Ang II activity 
. Further analysis of the interaction between Sesn2 and Ang II is needed to observe the potential advantageous downstream effects of the axis on the pathophysiology of hypertension.
Sesn2/Ang II/Nox axis in hypertension (created with BioRender.com
, accessed on 15 May 2023).
5. Sesn2, AMPK, and mTOR
Two protein complexes, mTORC1 and mTORC2 share the same serine/threonine protein kinase catalytic subunit, mTOR 
. These proteins participate in a range of functions including electrolyte homeostasis, cell growth, cell proliferation, immune system regulation, and activation of protein synthesis 
. Specifically, mTORC1 serves regulatory purposes as it acts in response to oxidative stress and changes in energy levels 
. The precise function of mTORC2 needs further examination. However, it has been reported to play a role in the regulation of renal tubular sodium and potassium transport 
. Persistent stimulation of mTORC1 serves as a signaling pathway in the development of fibrosis and collagen disposition, contributing to the development of hypertension 
. The increase in Ang II can also activate mTORC1; however, knowledge of this pathway is understudied 
. Chronic activation of mTORC1 can lead to the overactivation of protein synthesis, thus generating ER stress and the production of ROS. Sesn2 can interact and mitigate mTORC1 via disruption of the Ras homolog enriched in the brain (Rheb) and Ras-related GTPase A/B axis, two of the GTPases responsible for the activation of mTORC1 
. An upstream regulator of mTOR, AMPK can be activated by Sesn2 to mitigate these effects produced by the chronic stimulation of mTOR (Figure 3
. Further, AMPK activation by Sesn2 can influence overactive NOX4, decreasing the ROS production exhibited in hypertension 
Sesn2/AMPK/mTOR in hypertension (created with BioRender.com
, accessed on 17 May 2023).
6. Sesn2 Protein as a Therapeutic Modality for the Treatment of Hypertension
The details mentioned indicate the potential of Sesn2 as a therapeutic target for hypertension. A comprehensive understanding of the nature of Sesn2 and its upstream/downstream effects can give insight into its therapeutic potential. Currently, there are no known direct pharmacological correlates to the mechanism of Sesn2. A Sesn2 mimetic could be developed where the small molecule’s active sites have more affinity for the downstream targets, contributing to specificity. Furthermore, Sesn2 activators and inducers should be further investigated, as these could induce Sesn2 in non-oxidative stress conditions. This could prove advantageous in the early, or prophylactic treatment of disease.
As mentioned, an activator of Sesn2 is Nrf2. Nrf2 agonists such as sulforaphane and curcumin are under heavy investigation for their downstream antioxidant protein activation effects. An effective Nrf2 agonist has yet to be developed due to a lack of specificity. A delicate balance in ROS scavenging capabilities is of utmost importance. A drop in ROS can contribute to alleviating the progression of disease. However, drastic ROS scavenging levels or those that lack specificity could lead to the development of unwanted disease. For example, ROS are used in immune function. The hyper-targeting or removal of ROS function could lead to dysfunction of the immune system, allowing opportunities for pathogens to induce disease. The development of a high-specificity Nrf2 agonist could activate Sesn2 in non-oxidative or low-oxidative stress conditions, such as early or pre-hypertension. The Nrf2/Sesn2 pathway could lead to a viable early treatment modality for hypertension and warrants further examination.
Lastly, adeno-associated virus (AAV) vectors, an effective method for gene therapy delivery, could be utilized to favorably manipulate Sesn2 in hypertension. AAV vectors can replace genes, silence genes, edit genes, and knock-in genes 
. The use of the vectors could potentially increase Sesn2 expression to counteract the high amount of ROS production/oxidative stress exhibited in hypertension. Also, AAV vectors could favorably edit the gene for Sesn2, producing a Sesn2 protein whose active sites have a highly specific and effective affinity for their respective downstream targets such as NADPH oxidase and Ang II.