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Introduction

Heat shock proteins (HSPs) are an endogenous protein family associated with various cellular functions in tissues, which serve crucial roles in maintaining protein and cellular homeostasis, and protecting cells from damage (1–3). HSPs were initially named after the discovery of their response to cellular heat; however, further research has revealed that HSPs can be activated under conditions such as hypoxia, oxidative stress, infection and exposure to heavy metals, and that they can repair damaged proteins and protect them from damage (4–6). The molecular sizes of HSPs range from 10 to 150 kDa, and HSPs are roughly divided into HSP110, HSP90, HSP70, HSP60, HSP40 and small HSPs (sHSPs) based on their molecular weights. Notably, HSPs participate in co-translational or post-translational protein folding (7). The molecular sizes of sHSPs range from 12 to 43 kDa; sHSPs with a core α-crystallin domain include HSPB1/HSP27, HSPB2, HSPB3, HSPB4, HSPB5, HSPB6, HSPB7, HSPB8/HSP22, HSPB9 and HSPB10 (8). sHSPs are responsible for the binding of improperly folded protein substrates. Additionally, they can stabilize damaged proteins by exposing hydrophobic residues, and they further transfer these proteins to ATP-dependent chaperones or protein degradation machines, such as proteasomes or autophagosomes, in order to prevent protein denaturation, misfolding and abnormal aggregation (2,9–12).

HSPB8 was first described in human melanoma cells in 2000, at which time it was identified as being an H11 protein kinase (13). Due to its molecular weight being ~22 kDa, HSPB8 is also referred to as HSP22 (14). Initially, the investigation into HSP22 was limited to tumors; notably, it was demonstrated to be highly expressed in specific tumors, such as gastric cancer (15), breast cancer (16), ovarian cancer (17), hepatocellular carcinoma (18) and glioblastoma (19). Moreover, HSP22 has been shown to be highly expressed in breast cancer and ovarian cancer, and to promote the occurrence and development of tumors by regulating the proliferation and migration of tumor cells (16,17). Conversely, HSP22 is expressed at low levels in other tumor tissues or cell lines, such as melanoma and prostate cancer (20,21). By treating with demethylating agents, the apoptosis of tumor cells with a low expression of HSP22 can be induced (20–22). Furthermore, an exploration into sHSPs revealed that HSP22 is mainly expressed in skeletal muscle and the myocardium (9,23). In skeletal muscle, HSP22 may be involved in muscle development and repair processes (24,25). In addition, mutations or the abnormal expression of HSP22 may be closely related to the occurrence and development of certain muscle diseases, such as hereditary peripheral motor neuropathy (26). However, compared with in cardiac tissue, the stress protective effect of HSP22 in skeletal muscle may not be as significant; notably, there is evidence suggesting that myocardial ischemia can induce the expression of HSP22 in cardiac tissue in animal models and patients (27–29). In addition, the upregulation of HSP22 may protect myocardial cells from hydrogen peroxide (H2O2)-induced oxidative stress and cell death in vitro and reduce myocardial ischemic damage in vivo (30–33). Notably, the downregulation of HSP22 has been reported to increase stress-induced myocardial cell death, thus accelerating the transition to cardiac failure during cardiac overload (34). A lack of HSP22 can also disrupt cardiac energy metabolism homeostasis and increase oxidative damage, thus leading to cardiac dilation and dysfunction (35). These findings indicate the indispensable role of HSP22 in the heart; therefore, it may be considered a novel therapeutic target for cardiovascular diseases.

The present review aimed to extensively explore and analyze the role and function of HSP22 in regulating the potential mechanisms of cardiovascular disease. By systematically reviewing existing research results in various aspects, the key role of HSP22 in cardiovascular disease at the molecular, cellular and tissue levels is clarified, and its mechanism of impact on the occurrence and development of cardiovascular disease is demonstrated. In addition, the present study provides new perspectives and potential targets for the treatment and prevention of cardiovascular diseases by comprehensively evaluating the biological characteristics of HSP22, and the complexity of its interaction with the cardiovascular system.

Protective effect of HSP22 on myocardial cells

HSP22 is a transmembrane protein with a stable tertiary structure, which contains long α-helices and short β-curls that result in a high degree of stability (9,14). HSP22 is widely expressed in almost all tissues (14,36–38). Notably, HSPs serve an important ‘housekeeping’ role; therefore, any damage to the HSP network can be dangerous to cells. In the heart, HSP22 has been shown to be inducible under various endogenous or exogenous stimuli, and to be regulated by the upregulation of heat shock factor (HSF) transcription. Studies have shown that the activation of HSF1 and HSF2 is involved in cardiac development and regulates the expression of HSPs in cardiovascular diseases (39,40). In general, the transcription and expression of HSPs are unlikely to be impacted by HSF; however, under stress conditions, unfolded proteins may disrupt the interaction between the two proteins, thus inducing the activation and translocation of HSF and leading to the transcription of HSP22 (41,42). Notably, previous in vivo and in vitro studies have demonstrated a marked increase in HSP22 in the myocardium after acute and chronic ischemia, whereas it is not induced in the normal myocardium (27,28). In addition, the short-term overexpression of HSP22 adenovirus in pig hearts can reduce infarct size after ischemia-reperfusion (I/R) and upregulate myocardial inducible nitric oxide (NO) synthase (iNOS) (30). These data indicate that HSP22 is a stress-related protein that can be stimulated in the hypoxic adaptive myocardium. The inducement of this protein may have a cellular protective effect, thus preventing irreversible damage to the ischemic myocardium. Herein, the present study summarized the basic molecular mechanisms by which HSP22 participates in regulating myocardial cell protection (Fig. 1).

Figure 1. Molecular process via which HSP22 ameliorates cardiovascular disease. AMPK, 5′ AMP-activated protein kinase; BAG3, Bcl-2-associated homolog 3; HSP22, heat shock protein 22; iNOS, inducible nitric oxide synthase; OXPHOS, oxidative phosphorylation; ROS, reactive oxygen species; VCP, valosin-containing protein.

HSP22 protects the heart by regulating oxidative stress

iNOS is an enzyme that catalyzes the production of NO from L-arginine and serves an important role in the process of cardiac oxidative stress. Multiple studies have shown that the cardioprotective effect of HSP22 depends on the induction of iNOS. Depre et al (33) reported that the overexpression of HSP22 can induce the expression of iNOS in transgenic (TG) mice, thus serving as an effective method of ischemic preconditioning to protect the heart. In addition, iNOS inhibitors were shown to eliminate the cellular protective effect of HSP22 (33). Chen et al (30) also reported that HSP22 increases the expression of iNOS through the transcription factors NF-κB and STAT in isolated myocardial cells. Further research has revealed that the NO synthesis inhibitor L-NNA can inhibit the ability of HSP22 to reduce the infarct size of pigs (30). Qiu et al (34) reported that the absence of HSP22 impairs the nuclear and mitochondrial functions of STAT3 and reduces the expression of iNOS in cardiomyocytes under cardiac stress, thus indirectly indicating a significant correlation between HSP22 and iNOS expression. In addition, Lizano et al (43) reported that the expression of valosin-containing protein (VCP) in cardiomyocytes is highly associated with iNOS expression; as a substrate of Akt, VCP can mediate an increase in iNOS expression downstream of HSP22 via an NF-κB-dependent mechanism. These findings indicate that iNOS is an important mediator of the ability of HSP22 to protect the heart.

Another key component of cardiac oxidative stress involves reactive oxygen species (ROS), which are defined as reactive molecules or free radicals containing oxygen (44). These molecules or free radicals are usually produced during cellular metabolism and have high chemical activity. Common ROS include superoxide anions, H2O2, hydroxyl radicals and singlet oxygen (45–47). Low concentrations of ROS are involved in cellular signaling and regulation, such as cell proliferation, differentiation and immune responses (45). However, when the generation of ROS exceeds the antioxidant capacity of cells, it can cause oxidative stress, thus leading to oxidative damage to intracellular biomolecules such as DNA, proteins and lipids. Therefore, the maintenance of a balance of ROS is crucial for health. Multiple studies have shown that the upregulation of HSP22 in myocardial cells can reduce H2O2-mediated cell apoptosis by 60% (30–33). In addition, Qiu et al (34) investigated isolated mitochondria from the hearts of TG mice and reported that the overexpression of HSP22 weakened hypoxia-induced oxidative phosphorylation and ROS production. However, although HSP22 can protect mitochondrial function under stress conditions, long-term chronic overexpression may interfere with the normal function of mitochondria. Morin et al (48) reported that long-term chronic overexpression of HSP22 may affect the process of mitochondrial oxidative phosphorylation, thus leading to reduced ATP synthesis and increased ROS generation. The excessive production of ROS can cause damage to mitochondria, thus further exacerbating mitochondrial dysfunction and affecting the normal physiological function of the heart (49). When the heart is subjected to long-term pressure or injury stimulation, myocardial cells undergo hypertrophy to compensate for changes in heart function. HSP22 may be involved in this process; moreover, if it is upregulated for a long period of time, it may continue the process of myocardial hypertrophy and lose normal compensatory balance (48). Cardiac hypertrophy and fibrosis can cause a decrease in the elasticity and compliance of the heart, thus affecting its diastolic function and ultimately leading to heart failure. In addition, long-term chronic upregulation of HSP22 may accelerate the aging process of the heart (50). This effect may be related to the interference of HSP22 in mitochondrial function, as mitochondria are key organelles for cellular energy metabolism and signal transduction, and their dysfunction can lead to cellular aging and functional decline. The electrical activity of myocardial cells depends on the normal opening and closing of various ion channels, such as sodium, potassium and calcium channels (51). HSP22 may interact with ion channel proteins; additionally, when it is upregulated for a long period of time, it may alter the expression level, distribution or functional characteristics of ion channels, thereby affecting the metabolic processes of the heart (51). These studies emphasize the importance of HSP22 in regulating oxidative stress in cardiomyocytes.

HSP22 promotes cardiac autophagy and antiapoptotic effects

Autophagy is an important process in which cells clear damaged or excess organelles, proteins and other cellular components, which is crucial for maintaining cellular homeostasis and function (52–54). In the heart, autophagy helps to clear damaged mitochondria and proteins, thus preventing the accumulation of intracellular waste. HSP22 can protect myocardial cells from stressful stimuli (such as oxidative stress, I/R injury and toxins) by promoting autophagy, thereby increasing the tolerance and function of the heart (55–60). Bcl-2-associated homolog 3 (BAG3) is a cochaperone protein that is highly expressed in the heart, and extensive research has shown that HSP22 is functionally dependent on BAG3 (61–63). Arndt et al (61) and Carra et al (63) reported that HSP22 and its copartner BAG3 serve crucial roles in cardiac autophagy. HSP22 is responsible for identifying misfolded proteins, and BAG3 (at least partially through its proline-rich domain) may recruit and activate macrophage autophagy mechanisms that tightly bind to chaperone molecular substrates. Depre et al (33) also demonstrated that the synergistic effect of BAG3 and HSP22 induces autophagic degradation. Wu et al (35) reported that the absence of HSP22 can impair BAG3 expression and associated cardiac autophagy, disrupt cardiac energy metabolism homeostasis and increase oxidative damage. Liang et al (64) reported that the upregulation of HSP22 can increase the expression of EcBAG3 (a homolog of BAG3), whereas the knockdown of EcBAG3 can affect autophagy. These findings indicate that HSP22 has a crucial role in cardiac autophagy.

By regulating autophagy, HSP22 can reduce the activation of apoptosis-related proteins (such as Bax), thereby reducing myocardial cell apoptosis, which is particularly important under pathological cardiac conditions (64,65). Akt is a downstream effector of PI3K. Sui et al (31) reported that the upregulation of HSP22 increases PI3K activity, Akt phosphorylation, Smad 1/5/8 phosphorylation and [(3)H] phenylalanine incorporation, as well as causing a 70% reduction in cell apoptosis mediated by H2O2 in isolated muscle cells. Lan et al (66) reported that the upregulation of HSP22 in the heart can inhibit doxorubicin-induced cardiac injury, alleviate inflammation and reduce cardiac apoptosis by blocking TLR4/NLRP3 activation. Moreover, Yu et al (50) demonstrated that HSP22 can improve lipopolysaccharide-induced myocardial injury by inhibiting inflammation, oxidative stress and cell apoptosis. By contrast, a previous study suggested that HSP22 has dose-dependent and dual hypertrophic and proapoptotic functions in myocardial cells (29). In the cardiac myocytes of rats, HSP22 can induce hypertrophy at low doses via kinase-independent Akt activation, whereas at high doses, it can induce cell apoptosis via a protein kinase-dependent mechanism, particularly by inhibiting casein kinase 2 through interaction with this kinase and subsequent physical interactions (29).

HSP22 is responsible for subcellular redistribution

HSP22 is not only a companion protein but is also responsible for the subcellular redistribution of other proteins. Depre et al (67) reported that the upregulation of HSP22 increases the protein/DNA ratio in isolated neonatal rat cardiomyocytes by 37%. In this previous study, a heart-specific transgene of HSP22 driven by the α-MHC promoter was generated, thus resulting in an average 7-fold increase in HSP22 expression, accompanied by dose-dependent activation of the kinases Akt/PKB and p70 (S6) (67). Qiu et al (34) reported that HSP22 promotes STAT3 translocation to mitochondria, regulates mitochondrial function in isolated neonatal rat cardiomyocytes, and increases oxidative phosphorylation. Rashed et al (68) also demonstrated that the translocation of HSP22 and iNOS to the mitochondria is necessary for HSP22-mediated oxidative phosphorylation. HSP22 mainly aggregates in the perinuclear compartment and mitochondrial inner membrane, which provides the foundation for its interaction with other proteins to enter into the nucleus and mitochondria.

HSP22 enhances proteasome activity

Multiple studies have shown that HSP22 is closely related to the expression of proteasomes. A pioneering study by Depre et al (33) revealed that HSP22 can participate in the metabolic switch mechanism of ischemic hearts by promoting the activity of 5′ AMP-activated protein kinase (AMPK). HSP22 directly binds to Akt and AMPK, thus promoting their nuclear translocation and binding to multiple protein complexes, which stimulates the survival mechanisms of cell solutes and nuclei, and achieves a protective effect on the heart (33). In addition, HSP22-mediated cardiac hypertrophy promotes increased expression and activity of proteasomes, as well as their subcellular redistribution (69). The inhibition of proteasomes can prevent the increase in the protein synthesis rate that is observed after the upregulation of HSP22 or the addition of hypertrophic stimuli, thereby reversing cardiac hypertrophy (69). Wu et al (35) reported that HSP22 deficiency disrupts key regulatory enzymes for fatty acid (FA) transport and FA oxidation, thus disrupting FA metabolism, and leading to cardiac dilation and aging. These findings indicate a close relationship between HSP22 and the energy metabolism of proteasomes. Notably, it is still unclear as to how HSP22 regulates and enhances the activity of proteasomes in ischemic hearts.

Regulating HSP22 to improve cardiovascular disease

Based on the critical role of HSP22 in the heart, a number of studies have reported on the effects of drugs or cytokines that regulate HSP22 in cardiovascular disease.

Geranylgeranylacetone (GGA) can induce HSP22 to protect the heart

GGA, which is also known as teprenone, has been widely used as an oral anti-ulcer drug in Japan and China since 1984 (70). Notably, it has been reported that GGA can induce the upregulation of HSPs under stress conditions; however, its induction effect is weaker in the absence of stimulation (70,71). Multiple studies have shown that GGA serves a protective role in inflammation, ischemia, oxidative stress and the toxin response by increasing the expression of HSPs (72,73). In recent years, research on GGA and cardiovascular disease has focused on atrial fibrillation (AF) (Table I). Brundel et al (74) reported that the administration of heat shock and GGA before tachy-pacing in patients with paroxysmal AF can almost completely prevent tachy-pacing-induced myolysis. Notably, the upregulation of HSP27 may also provide complete protection against pacing-induced myolysis, which helps to limit its progression to persistent AF (74). Furthermore, additional studies have shown that HSP induction can prevent remodeling caused by tachycardia. In vitro experiments have shown that the protective effect of an atrial cell line (HL-1) on cardiomyocytes requires HSP27 induction and phosphorylation (75). In clinically relevant animal models, the oral HSP inducer GGA has a protective effect on AF (75). Sakabe et al (76) also reported that GGA can prevent atrial conduction abnormalities caused by ischemic arrhythmias and inhibit ischemic AF. Zhang et al (77) demonstrated that pretreatment with heat shock, or the HSP inducers GGA and BGP-15, can lead to endogenous HSP upregulation and prevent tachycardia-induced remodeling. Chang et al (78) demonstrated that GGA can reduce triggering activity, action potential duration dispersion and AF induction ability in the heart during heart failure by inducing HSP, and regulating ion channels and calcium homeostasis. Furthermore, van Marion et al (79) identified new GGA derivatives (especially GGA * −59), which can promote HSP expression, thereby preventing and restoring tachy-pacing-induced remodeling. Further research has demonstrated that GGA * −59 and recombinant HSPB1 can accelerate tachy-pacing-induced structural remodeling and the recovery of contractile dysfunction in HL-1 cardiomyocytes (80). GGA * −59 can also increase HSPB1 levels after tachy-pacing, inhibit HDAC6 activity, and restore contractile protein and microtubule levels. In addition, a previous study reported that 3 days of GGA treatment in the right and left atrial appendages of patients who underwent coronary artery bypass grafting was associated with increased levels of HSPB1 and HSPA1 expression, as well as increased levels of HSPB1 in muscle fibers (81). In addition, a recent study revealed that GGA can reduce myocardial cell stiffness and alleviate diastolic dysfunction in a rat model of metabolic syndrome by increasing myofilament binding to HSPB1 and HSPB5 (82). Although current research on the role of GGA in AF is detailed, reports on the regulation of HSP22 by GGA is currently limited.

Table I. Function and potential mechanism of GGA-induced HSP.

Table I.

Function and potential mechanism of GGA-induced HSP.

First author, year	Disease	Functions and potential mechanisms of GGA-induced HSP	(Refs.)
Brundel, 2006;	Paroxysmal	Upregulation of HSP27prevents myolysis and muscle remodeling caused by	(74,75)
Brundel, 2006	AF	tachycardia
Sakabe, 2008	AF	Prevents atrial conduction abnormalities and suppresses ischemic atrial fibrillation	(76)
Zhang, 2011	AF	Promotes endogenous HSP upregulation and prevents tachycardia remodeling	(77)
Chang, 2013	Arrhythmia	Induces HSP and regulates ion channels and calcium homeostasis, reducing triggering activity, action potential duration dispersion, and AF induction ability in heart failure	(78)
van Marion, 2019	AF	Promotes HSP expression to prevent and restore remodeling induced by tachypacing	(79)
Hu, 2019	AF	Increased HSPB1 levels inhibit HDAC6 activity and restore contractile protein and microtubule levels	(80)
van Marion, 2020	Undergoing	GGA treatment is related to higher HSP27 and HSP70 expression levels in	(81)
	CABG	RAA and LAA of patients undergoing CABG surgery, and higher HSP27 levels in the myofilaments
Waddingham, 2023	Cardiac metabolic syndrome	Reduces myocardial cell stiffness and alleviates diastolic dysfunction by increasing the binding of HSPB1 and HSPB5 to myofilaments	(82)

[i] AF, atrial fibrillation; CABG, coronary artery bypass grafting; GGA, geranylgeranylacetone; HSP, heat shock protein; LAA, left atrial appendages; RAA, right atrial appendages.

In 2009, Sanbe et al (83) first proposed that the oral administration of GGA can increase the expression levels of HSP22 and HSPB1 in the hearts of HSPB5 R120G TG (R120G TG) mice. Compared with in untreated R120G TG mice, R120G TG mice treated with GGA exhibited reduced heart size and interstitial fibrosis, as well as improved cardiac function and survival rates. In addition, heart-specific TG mice expressing HSP22 were constructed; the overexpression of HSP22 was shown to lead to a decrease in the formation of amyloid oligomers and aggregates, thereby improving cardiac function and the survival rate (83). Marunouchi et al (84) reported that treatment with GGA at 2–8 weeks after myocardial infarction in rats can alleviate the decrease in the mitochondrial HSPB1 and HSP22 content, and that oral administration of GGA can maintain the mitochondrial energy production capacity and cardiac pump function during heart failure. These findings indicate that GGA treatment may induce the expression of sHSPs in the infarcted heart, which helps to maintain mitochondrial function and improve cardiac contractile function. Recently, a study published by our team revealed that GGA can induce the expression of HSP22, protect the vascular endothelium of mice from oxidized low-density lipoprotein damage, and block the development of atherosclerosis (85). Although it is still unclear as to how GGA regulates HSP22, this evidence demonstrates the significant potential of GGA and HSP22 in cardiovascular disease (Table II).

Table II. Medications or cytokines that control HSP22 to treat heart conditions.

Table II.

Medications or cytokines that control HSP22 to treat heart conditions.

First author, year	Drugs or cytokines	HSP22-associated functions and potential mechanisms	(Refs.)
Sanbe, 2009	GGA	Increasing the expression levels of HSP22 and HSPB1 in the heart leads to a decrease in the formation of amyloid oligomers and aggregates, reducing heart size and interstitial fibrosis, and improving heart function and survival rate	(83)
Marunouchi, 2014	GGA	Reduces the decrease in mitochondrial HSPB1 and HSP22 content, maintains mitochondrial energy production capacity and cardiac pump function	(84)
Gong, 2019	GGA	Induces HSP22 expression and protects mouse vascular endothelium from ox-LDL damage	(85)
Lizano, 2013	VCP	Mediates the increase of iNOS expression downstream of HSP22 through an NF-κB dependent mechanism	(43)
Jiang, 2017	microRNA-126a-5p	Promotes in vivo I/R injury by inhibiting the expression of HSP22	(86)
Ren, 2020	ZBTB20	The expression of HSP22 is significantly reduced in ZBTB20-null myocardium	(87)
Martin, 2022	JG-98	Reduces autophagic flux, and alters the expression of BAG3 and HSP22	(88)
Cheng, 2023	DUSP12	Reduces cell apoptosis and oxidative stress in myocardial I/R injury through HSP22-induced mitochondrial autophagy	(89)

[i] BAG3, Bcl-2-associated homolog 3; DUSP12, dual-specificity phosphatase 12; GGA, geranylgeranylacetone; HSP, heat shock protein; iNOS, inducible nitric oxide synthase; I/R, ischemia-reperfusion; ox-LDL, oxidized low-density lipoprotein; VCP, valosin-containing protein.

Other cytokines that regulate HSP22 to improve cardiovascular disease

In addition to GGA, numerous studies have reported the regulatory effects of other molecules on HSP22. Lizano et al (43) reported that the Akt substrate VCP may mediate an increase in iNOS expression downstream of HSP22 via an NF-κB-dependent mechanism. Via bioinformatics analysis combined with experimental validation, Jiang et al (86) demonstrated that microRNA-126a-5p is upregulated in myocardial I/R model mice and promotes in vivo I/R injury by inhibiting the expression of HSP22. Ren et al (87) reported that the lack of the zinc finger protein ZBTB20 reduces the cardiac ATP content, and impairs the enzyme activity of mitochondrial complex I and the L-type calcium current density in myocardial cells. Moreover, the expression of HSP22 was shown to be significantly reduced in the ZBTB20-null myocardium. Martin et al (88) reported that treatment with JG-98 (a small-molecule therapeutic agent applied to tumors) can reduce autophagic flux, and alter the expression of BAG3 and several binding partners involved in BAG3-dependent autophagy, including SYNPO2 and HSP22. In addition, a recent study demonstrated that the upregulation of dual specificity phosphatase 12 can reduce cell apoptosis and oxidative stress in myocardial I/R injury via HSP22-induced mitochondrial autophagy (89). Various studies have shown that HSP22 is involved in regulating the physiological and pathological processes of the heart, although its molecular mechanism remains largely unknown (Table II).

Perspectives

The present study provides an overview of new research and progress on the role of HSP22 in cardiovascular diseases; however, several issues require further investigation. First, as described in the present review, long-term chronic upregulation of HSP22 in the heart may increase oxidative phosphorylation and mitochondrial ROS production, which ultimately leads to aging and a shortened lifespan (48). More research is still needed to verify the potential risks of the long-term chronic upregulation of HSP22, which will provide further insights into the efficacy and safety of HSP22 in the heart. Second, an appropriate increase in the expression of HSP22 within a certain range can increase the resistance of animals to high glucose, high fat and other stress factors, as well as protect endothelial cells from damage and reduce the likelihood of atherosclerosis (85). Although, to the best of our knowledge, there are currently no direct studies on the effects of the upregulation of HSP22 in animals, in accordance with the characteristics of the HSP family, its upregulation may lead to an imbalance of protein homeostasis in cells, thus resulting in a series of adverse consequences (90,91). Therefore, in practical applications, it is necessary to carefully control the expression levels of HSP22. Future research can explore the specific mechanisms of the effects of different doses of HSP22 on animals, and determine how to prevent and treat related diseases by regulating the expression of HSP22.

Third, a previous study reported that HSP22 is also upregulated during the aging process in fruit flies (92); however, the age-related expression of HSP22 in the heart is still debatable. Fourth, the role of GGA-induced HSP22 in cardiovascular disease has not been well explored and whether GGA activates HSP22 differently in various cardiovascular disorders is still up for debate. As a HSP inducer, GGA can trigger the expression of numerous HSPs, including HSP22, and has broad-spectrum pharmacological effects; however, the pathophysiology and etiology of various cardiovascular diseases differ, which could result in variations in how GGA induces HSP22 in various conditions. To confirm the precise discrepancies, more investigation is required. Fifth, although the cardiovascular benefits of HSP22 have been demonstrated in animal experiments, no relevant clinical studies are available regarding these effects. Through large-scale clinical sample analysis, it may be possible to identify specific biomarkers related to HSP22 function that can be easily detected in human blood, urine or tissues. These biomarkers could be used for early diagnosis, disease monitoring and treatment efficacy evaluation of diseases, thus helping to screen the most suitable patient population for HSP22-related treatment. Based on the mechanism of action and structural characteristics of HSP22, drugs that can specifically activate HSP22 gene transcription or increase its protein activity can be developed in the future; alternatively, inhibitors or agonists targeting key molecules in the HSP22 signaling pathway can be developed. In addition to common intravenous and oral administration methods, specific administration methods, such as local myocardial injections and transdermal administration, could also be explored to increase the concentration of drugs in the heart, enhance treatment efficacy, and reduce systemic side effects. Furthermore, a critical analysis of the potential clinical application of HSP22 in cardiovascular disease is required. Although HSP22 has multiple biological functions and protective effects, its specific application value and safety still require further verification. In future research, a deeper understanding of the regulatory mechanisms, pathways of action, and interactions between HSP22 and the cardiovascular system is required to provide more accurate and effective strategies for the treatment and prevention of cardiovascular diseases.

Finally, a number of patients with cardiovascular disease take medications that may cause gastrointestinal side effects; thus, GGA (as a gastric mucosal protector) may have potential in regulating HSP22 to improve cardiovascular disease. In the future, the specific mechanism by which GGA affects cardiovascular disease should be further clarified, and its role and effects in different types of cardiovascular diseases should be explored. In addition, no specialist research has yet been done on how GGA interacts with other widely used medications to treat heart disease. The safety and efficacy of GGA in combination with other cardiovascular drugs warrant further investigation. In the future, by measuring the concentration and time curve of GGA and its metabolites in the body, the metabolic process and characteristics of GGA in the body can be understood, thus providing a basis for formulating reasonable medication plans. By combining both in vitro and in vivo experiments, the interactions between GGA and other heart disease treatment drugs, including metabolic and pharmacological interactions, can be investigated. In addition, research in genetics and pharmacology can be used to understand the differences in response to GGA among different patients and the reasons for these differences, thus providing a scientific basis for personalized medication. It should be noted that, at present, there is no well-known substitute for GGA-induced HSP22. As aforementioned, certain cytokines or small molecule substances have the capacity to trigger HSP22; nevertheless, there is little data to confirm their safety and effectiveness. More optimal, secure and efficient substitutes for GGA-induced HSP22 expression may be discovered in the future as studies into the induction mechanism of HSP22 continue and new drugs are developed.

Acknowledgements

Not applicable.

Funding

This work was supported by the National Natural Science Foundation of China (grant no. 82160085) and the Key Science and Technology Innovation Projects of Jiangxi Provincial Health Commission (grant no. 2024ZD007).

Availability of data and materials

Not applicable.

Authors' contributions

YC and YW were responsible for study conception and design. YC and ML wrote the manuscript and were responsible for making revisions. Data authentication is not applicable. All authors read and approved the final version of the manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References