MicroRNAs (miRNAs) are endogenous small non-coding RNAs composed of approximately 22 nucleotides that directly regulate over 30% of genes. They inhibit the translation of messenger RNA (mRNA) or promote mRNA degradation either by annealing complementary sequences in the 3’ untranslated regions or interacting with the coding sequence (CDS) (1,2). Moreover, miRNAs are drastically upregulated during pathological stress caused by several diseases, thus they have been investigated as potential biomarkers in cancer, autoimmune diseases, cardiovascular diseases and other diseases. For this purpose, these biomarkers have been identified in peripheral blood, saliva and urine. It is worth noting that research has detected the selective release of some premature and mature miRNAs from cells to the bloodstream via exosomes, microvesicles or protein complexes (3,4).
Among the miRNAs involved in the pathogenesis of cardiovascular diseases, miRNA-208 (miR-208) is one of the significant genes linked with the pathogenesis of myocardial hypertrophy, arrythmias, myocardial infarction, myocardial fibrosis, coronary atherosclerosis and heart failure (5,6). Additionally, miR-208 consists of two subtypes, miR-208a and miR-208b, both genes of which are located within the human chromosome 14 (7).
As cardiac-enriched miRNAs, miR-208a and miR-208b are highly chamber-specific with their host genes. To be more specific, miR-208a is encoded within an intron of the alpha-cardiac muscle myosin heavy chain gene (Myh6) and both of them are atria-specific. Meanwhile, miR-208b and its host gene the beta-cardiac muscle myosin heavy chain gene (Myh7) are ventricle-specific (7). Under physiological conditions, the expression levels of miR-208a and miR-208b are paralleled with their host gene transcription patterns. However, under pathological stress, dissociations may occur. Previous research projects have explored the molecular mechanisms regulating the expression of miR-208 in cardiovascular diseases. In the present review, we determine the regulation mechanism of miR-208 and the role it plays in the pathogenesis of cardiovascular diseases.
We performed online search of medical literature published in an English Language Format through PubMed database over the past two decades, using a combination of text words and MeSH (Medical Subject Headings) terms: “microRNA-208”, “miR-208”, “microRNA”, “mechanism”, “function” and “cardiovascular diseases”. We selected articles that featured miR-208 in cardiovascular diseases models and patients. We then selected the most relevant articles based on a subjective appraisal of their quality and mechanistic insight that could be relevant to the regulatory molecular pathway of miR-208. Full texts of the retrieved articles were accessed.
No statistical analysis or comparisons, no grouping and no power calculations were conducted due to the heterogeneity of the studies. This study comprises a narrative synthesis of the available primary research studies, systematic reviews and meta-analyses in this area.
The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Shenzhen Children’s Hospital (NO.: 202003802) and informed consent was waived as there were no patients involved.
Molecular mechanisms involved in miR-208 regulation
THAP1 and myostatin
Thyroid hormone-associated protein 1 (THAP1) and myostatin are negative regulators of muscle growth and hypertrophy, which are both targeted by miR-208, expressed in the myocardial tissue, controlling heart remodeling and myocardial fibrosis by regulating the expression of β-MHC in response to various stimuli (8,9).
Thrap1 as a part of the thyroid hormone nuclear receptor complex influences gene transcription either positively or negatively (10). Data have proven that miR-208 participates in the pre-transcription level of thyroid hormones, which modulates the expression of proteins related to cardiac hypertrophy, prevents collagen deposit and increases collagen removal (11). Furthermore, postpartum thyroid hormone (T3) signaling stimulates α-MHC while inhibiting β-MHC. Therefore, in the case of hypothyroidism or blockade of T3 biosynthesis with propylthiouracil (PTU), a decrease in the level of thyroid hormone induces upregulation of β-MHC, leading to a decline in cardiac performance.
Myostatin, also known as growth differentiation factor 8, is expressed in the cardiomyocytes and Purkinje fibers of the heart as an inhibitor of skeletal muscle growth (12,13). Besides, activation of the myostatin receptor inhibits the activity of AKT, a protein kinase B known as a major determinant of muscle protein synthesis and cell proliferation (12). Myostatin also inhibits myocardial proliferation and contractility, and induces fibrosis by stimulating fibroblast proliferation and survival (14). Also, it helps to maintain cardiac energy homeostasis mainly by regulating the myocardium’s oxidative metabolism, and prevent pathological cardiac hypertrophy (15).
Cyclin-dependent kinase inhibitor (P21)
Cyclin-dependent kinase inhibitor 1A (p21), a regulator of cell cycle progression at G1, is one of the targets of miR-208, and is upregulated by myostatin (18,19). Upregulation of the p53-p21 pathway controls cardiomyocyte hypertrophy and apoptosis in diabetic cardiomyopathy, and is imperative in the endothelial cell senescence induced by disturbed flow (20,21). As a result, miR-208 probably plays a major role in the development of diabetic cardiomyopathy, reduces migration and interrupts arterial repair by regulating the p21 gene. Reduction of miR-208 expression promotes the production of ROS (Reactive oxygen species) essentially by targeting p21, which then leads to cardiomyocyte apoptosis. In spite of its effects on cardiomyocytes, miR-208 also participates in insulin-induced vascular smooth muscle cell (VSMC) proliferation via downregulation of p21 (22).
Med13 and Mef2 axis
The complex mediator’s subunit MED13 (Thrap1, thyroid hormone receptor associated protein-1) of transcription is directly targeted and negatively regulated by miR-208a in the heart. MED13 downregulates a series of genes involved in cellular metabolism including the SREBP, RXR and PPARγ, which controls gene transcription related to thyroid hormone as a negative regulator of metabolism (23-25). Data have demonstrated that overexpression of MED13 in the heart or pharmacologic inhibition of miR-208a increases the metabolic rate, confers resistance to obesity, enhances insulin sensitivity and decreases plasma lipid levels (26).
Another regulator of metabolism, myocyte enhancer factor 2 (Mef2), regulates contractile and angiogenic genes, as well as the development of the right ventricle. The miR-208-Mef2 axis induces decompensation of the right ventricular function in a pulmonary hypertension rat model. There is a negative feedback loop through which Mef2 inhibits miR-208 expression by regulating its host α-MHC gene transcription. Consequently, the expression and activity of Mef2 is inhibited via the MED13/NCoR1 complex. This drives the transition from the compensating phase of right ventricular hypertrophy towards the decompensation phase as the self-limiting feedback loop is terminated (27).
SOX6, SP3, Purβ, HP1β
The sex determining region y-related transcription factor 6 (SOX6) is a member of the D sub family of the sex determining region Y (SPY)-box-related transcription factors. It is a Myh7 transcriptional repressor, which is preferentially inhibited by miR-208b. SOX5 and SOX6 both belong to the SoxD group and have a long N-terminal sequence containing a coiled-coil domain that enables them to heterodimerize with each other (28). Compared with SOX6, SOX5 is preferentially repressed by miR-208a. Moreover, SP3 is another Myh7 repressor found in skeletal muscles which can only be reduced considerably by miR-208a (29).
In HL-1 cells, miR-208b overexpression enhances fetal Myh7 expression by inhibiting the transcriptional repressors SOX6 and SP3. Based on this fact, it can be concluded that miR-208 overexpression supports the adaptive transcriptional switch from fast to slow contractile myosin genes in human myofibrils (30). A positive feedback loop may be present between miR-208b and upregulated Myh7 in injured cardiac tissue since fetal Myh7 is co-expressed with its intronic miR-208b.
SOX6 contains a conserved high-mobility-group DNA-binding domain, and acts as a crucial tumor-suppressor gene in the proliferation of esophageal cell carcinoma (ESCC) (31,32). Considering that SOX6 mRNA is a direct and functional target of miR-208, experimental results on ESCC suggested that miR-208 may influence the SOX6-mediated signaling pathway and thus play a role in promoting cell proliferation, tumorigenicity and cell cycle progression in ESCC (33). In this pathway, miR-208 negatively regulates SOX6, eventually leading to downregulation of p21, upregulation of cyclin D1 and phosphorylation of the Rb gene. However, ascertaining whether the same pathway exists in cardiomyocytes and endothelial cells requires further exploration.
High-volume swim training has been associated with decreased miR-208 expression and increased SOX6, MED13, SP3, Purβ and HP1β expression levels (17). These increased molecules are all repressors of β-MHC and targets of both miR-208a and miR-208b, responsible for the regulation of cardiac metabolic and contractile adaptation via exercise. Specifically, Purβ (purine-rich element binding protein B) represses the expression of ACTA2, which stimulates myofibroblast proliferation and differentiation in fibrotic diseases (34). Likewise, SP3 and HP1β both modulate histone deacetylase (HDAC) expression, which has a regulatory effect on cardiac remodeling. Class II HDACs are calcium-sensitive repressors of the MEF2 transcription factor (35), which boosts the expression of slow myofiber genes. Since miR-208 exerts repressive effects on HP1β and the latter is the corepressor of class II HDACs, the repressive influence of class II HDACs on MEF2 could be possibly diminished under the impact of miR-208, hence the expression of slow muscle genes is promoted (36).
Nuclear receptors PPARβ and PPARα
The principal function of peroxisome proliferative-activated receptors (PPARs) is to regulate the transcription of several genes related to cellular metabolism. Given that both PPARα and PPARβ are modulated by miR-208b in skeletal muscles, miR-208b is probably involved in modification of the metabolic state as well (26).
PPARα is expressed primarily in the liver, intestines, brown adipose tissues, and heart, which are all organs carrying out elevated levels of fatty acid catabolism (37). PPARα is considered as a short-lived protein as it gets ubiquitinated and degraded proteasomes. Ligand binding confers protective effects on PPARα, which only lasts for a few hours before PPARα is rapidly degraded (38). Additionally, PPARα overexpression in the heart leads to metabolic cardiomyopathy as well as hepatic insulin resistance (5). PPARβ is also ubiquitinated without ligand, but the protective effect produced by ligand binding persists as long as the latter is present (39).
PPARβ increases the level of miR-208b by activating transcription of the Myh7 and Myh7b genes, thereby leading to series of slow-twitch contractile muscle protein gene expression (40). In contrast, PPARα inhibits Myh7/miR-208b expression in muscle tissues.
It has been discovered that activation of either PPARα or PPARγ prevents proliferation and angiogenic activity in endothelial cells, while PPARβ exerts opposite effects under physiological conditions (41,42). Activation of the PPARβ signaling pathway enhances VEGF-A expression and angiogenesis in skeletal muscles and the heart via the activation of direct transcription or interaction with the PI3K/AKT pathway through which the capillary density increases (43,44). Its activation also prevents apoptosis of endothelial cells (45). Besides, PPARβ activation or overexpression inhibits inflammation through the transrepression of proinflammatory genes, whereas deletion of PPARβ aggravates the inflammatory state (46). Thence, this evidence points out that there may be a potential relationship between miR-208b and endothelial function through the regulation of PPARs. Withal, more studies are needed to verify this connection.
TGF-β1, Endoglin and Collagen I
It is well-known that miR-208 is positively correlated with cardiac fibrosis, which is characterized by the myocardial collagen volume fraction in human dilated cardiomyopathy (47). Experiments carried out on rat heart cells demonstrate that TGF-β induces miR-208a expression under mechanical stretch conditions, and elevated miR-208a expression levels consequently encourage the expression of endoglin and stimulate collagen I formation, during which the cardiomyocytes differentiate into myofibroblasts, resulting in cardiac fibrosis (48). The discovery of specific sites complementary to miR-208a on the endoglin promoter sequences indicates that miR-208a may directly target endoglin throughout the pathogenesis of cardiac fibrosis. Fetal cardiomyocytes contain endoglin but absent adult ones do not, and it has been linked to the development vascular and other diseases (49). It is an integral membrane glycoprotein and a co-receptor of TGF-β1 and TGF-β3, and it is highly expressed on proliferating vascular endothelial cells (50). As a TGFβ coreceptor, endoglin enhances TGF-β1 signaling by phosphorylating Smad3 (small mother against decapentaplegic protein) and binding BMP9 (bone morphogenetic protein 9) with high affinity. In this manner, endoglin stimulates the synthesis of collagen by cardiac fibroblasts, thus promotes cardiac fibrosis in pressure overload models (51).
Connexin and GATA4
GJA5 encoding Connexin40 (Cx40), associated with chronic atrial fibrillation in humans, is a potential target of miR-208a-3p (52). Connexin proteins are gap junction proteins indispensable for the orderly propagation of electrical impulses throughout the heart, and are closely related with various chronic human heart conditions leading to arrythmias and sudden death. Furthermore, Cx40 is expressed restrictedly on the atria and specialized cardiomyocytes consisting of the His bundle and Purkinje fibers, which is regulated by miR-208a (53). Data have confirmed that Cx43 is also regulated by miR-208 (30).
Besides, miR-208a directly targets the cardiac transcription factor GATA4 by specifically targeting its 3’ UTR. GATA4 is a transcriptional cofactor expressed within the cardiac conduction system of the adult heart. It participates in transactivating serum response factor-dependent promoters, which includes Cx40. Through this molecular mechanism, miR-208a’s gain- and loss-of-function are associated with arrhythmias (54). In addition, GATA4 is involved in the pathogenesis of cardiac hypertrophy, serving as a marker of myocyte hypertrophy and fibrosis, which is consistent with the cardiac hypertrophic effect induced by miR-208 (16,55).
COL1 and ACTA2
Elevated concentration of miR-208 in the plasma is correlated with myocardial infarction, the most evident pathogenic feature of which is the accumulation of collagen synthesized by cardiac fibroblasts, leading to post-infarction myocardial fibrosis. Research has established that miR-208b is downregulated in myocardial infarction rat models and its overexpression inhibits the expression of both COL1 and ACTA2 (the gene encoding smooth muscle α-actin) by directly targeting and inhibiting GATA4, which ultimately leads to the suppression of post-infarction myocardial fibrosis (56).
COL1A1 and ACTA2 are both pro-fibrotic genes related to fibrosis, a disease characterized by excessive synthesis and accumulation of extracellular matrix (ECM) proteins in organs such as the skin, liver, lung, kidney and heart (57,58). In this pathogenic process, the myofibroblasts are responsible for producing the majority of the ECM, characterized by de novo expression of smooth muscle α-actin (SM α-actin) and abundant ECM, especially type I collagen (COL1A1) (59). COL1 encoded by COL1A1 and COL1A2, is found increased in myocardial fibrosis and is usually used as a marker of fibrosis. Overexpression of miR-208b represses COL1A1 transcription and COL1 synthesis, which in turn suppresses the progression of fibrosis.
ACTA2 is highly correlated with fibrosis in different diseases. It has been found to be upregulated at both mRNA and protein levels after myocardial infarction and repressed by miR-208b overexpression (60). Since SM α-actin is typically expressed in the VSMC and conducive to vascular motility and contraction, mutations in its coding gene ACTA2 could cause various vasculopathies such as thoracic aortic aneurysm and aortic dissection, premature coronary artery disease and ischemic stroke (61). Another study centered on thoracic aortic aneurysms and dissections revealed that ACTA2 is related to the mediation of angiotensin II (AngII) induced apoptosis, possibly by affecting the expression of Bax and Bcl-2. Knocking out ACTA2 enhances the phonotypic modulation and apoptosis regulated by AngII in vascular smooth muscle cells, which consequently leads to a more vulnerable vascular wall and even vascular rupture (62). Therefore, overexpression of miR-208b probably grants a protective effect on blood vessels via ACTA2 inhibition.
Type 1 Angiotensin II Receptor (AT1R)
Hyperthyroidism induces cardiac hypertrophy by activating Type 1 angiotensin II receptors (AT1R), whereas pharmacologic blockade of AT1R markedly inhibits the cardiac hypertrophy induced by increased levels of thyroid hormone (TH) (63). AT1R has a positive effect on the expression of cardiac miR-208a/α-MHC in hyperthyroidism but is irrelevant to the level of miR-208b/β-MHC, which corresponds with rising miR-208a and falling miR-208b expression in TH-induced cardiac hypertrophy. Moreover, cardiac miR-208a enhances obesity, and its inhibition with subsequent increase in MED13 has been proven to be associated with attenuated weight gain despite leptin resistance (64).
Bax and PI3K/AKT Pathway
The PI3K/AKT pathway is a widely reported pathway conferring protection against cardiac hypertrophy and apoptosis (65). Abnormal activation of the PI3K/AKT signaling pathway was reported to be a negative feedback in response to abnormal stimuli (66,67). In respect of PI3Ks, class Ia PI3Ks are imperative for physiological hypertrophy. They emphatically adjust the heart’s size via the Akt pathway while class Ib PI3Ks negatively influence the heart’s contractile function (68).
As a serine/threonine protein kinase, AKT1 contributes to the net protein accumulation needed for cardiac hypertrophy by inhibiting the vitality of the forkhead box protein O3 (FOXO3) (69). Similarly, Akt signaling is also crucial in normal vascular patterning and remodeling via fine-tune control in endothelial cells (70).
In an experiment on rats, specimens transfected with Ad-anti-miR-208 exhibited a 2-fold decrease in vascular endothelial growth factor (VEGF) mRNA levels (27). Considering that overexpression of PI3K and AKT induces transcription of VEGF and promotes formation of new blood vessels (71), the results of this experiment probably indicate an inducive effect of miR-208 on VEGF through activation of the PI3K/AKT pathway in vascular homeostasis.
Phosphorylation of PI3K and AKT was significantly decreased under hypoxic conditions, but increased when the cell was transinfected with miR-208b mimics. This can be explained by the fact that miR-208b activates the PI3K/AKT pathway by directly downregulating Bax and further represses Bax expression after activating the PI3K/AKT pathway, through which miR-208b exerts its myocardioprotective effects (72).
SERCA2 and L-type Ca2+ channel subunits
Increased local (Ca2+ sparks) and global spontaneous Ca2+ released from the sarcoplasmic reticulum (Ca2+ waves) are associated with either chronic or paroxysmal atrial fibrillation (73,74). Studies on HL-1 myocytes and myocytes isolated from chronic atrial fibrillation (CAF) patients report that abnormal miR-208b expression levels repress the expression and function of L-type Ca2+ channel subunits (α1c and β2 encoded by CACNA1C and CACNB2 genes respectively) and the sarcoplasmic reticulum-ATPase Ca2+ pump (SERCA2), serving as an essential mediator in Ca2+ handling dysfunction during atrial remodeling (30). The CAF-associated increase of miR-208b promotes ICa,L downregulation by silencing its channel expression. Thus, miR-208a significantly reduces the frequency of Ca2+ sparks while miR-208b completely abolishes it. Concerning the negative effects on SERCA2 levels, both miR-208a and miR-208b remarkably reduce Ca2+ transient decay.
Nemo-like kinase (NLK), as an evolutionary conserved serine/threonine protein kinase, and an inhibitor of the Wnt/β-catenin signaling pathway, which plays multifunctional roles in cellular regeneration, proliferation and differentiation of cardiomyocytes (75).
NLK is a direct target of miR-208 and its expression is suppressed by the overexpression of miR-208 (76). It acts a maladaptive signaling effector in the heart as its deletion was shown to protect the mouse’s heart from remodeling induced by pressure overload and infarction. Furthermore, NLK enhances the stability and activity of p53 in response to DNA damage by revoking MDM2-mediated p53 ubiquitination and degradation (77). Since p53 is fundamental for cell cycle arrest, DNA repair and apoptosis induced by genotoxic and cellular stress (78,79), the relationship between miR-208 and these pathological molecular mechanisms is probably due to the downregulation of NLK and the corresponding alteration incurred by p53. This inference has been proven by the experiment carried out on rat heart cells, which brought to the conclusion that miR-208a promotes the apoptosis of AngII-induced cardiomyocytes by inhibiting NLK (80).
ROR2 (receptor tyrosine kinase-like orphan receptor 2 gene)
The receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a Wnt5a receptor since it belongs to the receptor tyrosine kinase family. It has been reported as not only a cell surface marker expressed by human mesenchymal stem cells with the potential for cartilage formation, but also a marker of mesodermal progenitors of all major cardiovascular lineages (81-83). Nonetheless, ROR2 expression is limited to human fetal hearts from the first trimester and completely absent in adult human myocardial tissues (84).
AngII enhances VSMC proliferation and migration by augmenting ROR2 expression and stimulating the RhoA signaling pathway (85). Meanwhile, knockdown of the ROR2 receptor markedly suppresses cell migration in endothelial cells, and reduces cholesterol accumulation as well as inflammatory responses in VSMCs during the progression of atherosclerosis (86,87). Based on the fact that miR-208b has been identified to inhibit osteosarcoma progression by directly targeting and downregulating ROR2 receptors (88), it would be reasonable to assume that miR-208 may also be involved in vascular homeostasis via ROR2 regulation. Unfortunately, there is no literature illustrating the direct relationship between miR-208 and ROR2 in cardiovascular diseases so far, thus further investigation on this topic is warranted.
In a nutshell, miR-208 is a miRNA mainly expressed in the heart, and closely related to cardiovascular diseases. Regarding the pathogenesis of cardiac hypertrophy, overexpression of miR-208 inhibits THAP1 and myostatin, which are both negative regulators of muscle growth and hypertrophy. Furthermore, overload exercise may decrease miR-208 expression, resulting in increased expression of SOX6, MED13, SP3, Purβ and HP1β, which eventually influences cardiac metabolism and contractile adaptation. The miR-208-Mef2 axis was found to induce decompensated right ventricle hypertrophy in the pulmonary hypertension rat model. Nevertheless, miR-208 exerts its effects predominantly through inhibition of p21 and NLK in the pathogenesis of myocardial infarction. Moreover, miR-208 is associated with arrhythmias, through the regulation of Cx40 and Cx43. Additionally, abnormal levels of miR-208 lead to suppression of L-type Ca2+ channel subunits and SERCA2, affecting the handling function of Ca2+ during atrial remodeling. A strong correlation has been established between miR-208 also and cardiac fibrosis via endoglin regulation and collagen I expression. Overexpression of miR-208b inhibits the expression of COL1 and ACTA2 by inhibiting GATA4, hence hindering the progression of post-infarction myocardial fibrosis. With respect to vascular diseases, miR-208 exerts its various functions by acting on proteins associated with inflammation, endothelial apoptosis, VSMC proliferation and migration, including the PPAR, ACTA2, ROR2 and PI3K/AKT pathways.
In conclusion, miR-208 plays a pivotal role in the pathogenesis of myocardial hypertrophy, myocardial infarction, arrhythmias, myocardial fibrosis and dysfunction of blood vessels, implying that it could be implemented into routine clinical practice as a valuable biomarker and therapeutic target for cardiovascular diseases. It has recently been identified as a potential plasma biomarker for coronary artery disease (89). Further exploration of the potential link between miR-208 and cardiovascular diseases would provide more valuable diagnostic and therapeutic insights.
Funding: This research was supported by the National Natural Science Foundation of China [grant number 81870364], Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties [grant number SZGSP012] and Shenzhen’s Sanming Project [grant number SZSM20162057].
Conflicts of Interest: The authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jxym-21-8). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Shenzhen Children’s Hospital (NO.: 202003802) and informed consent was waived as there were no patients involved.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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Cite this article as: Zhang XT, Xu MG. Potential link between microRNA-208 and cardiovascular diseases. J Xiangya Med 2021;6:12.