Unveiling the Possible Role of Toll-like Receptors in Myocardial Hypertrophy

 

Shikha Virk^1,2, Anshul Sharma³, Rupinder Sodhi⁴, Onkar Bedi⁵, Sunny Dhiman⁶*

¹Chitkara College of Pharmacy, Chitkara University, Rajpura,Punjab, India.

²Department of Pharmacology, Chandigarh College of Pharmacy, CGC Landran Mohali, Punjab 140307 India.

³Department of Pharmacognosy, Chandigarh College of Pharmacy, CGC Landran Mohali, Punjab 140307 India.

⁴Department of Pharmacology Chandigarh College of Pharmacy, CGC Landran Mohali, Punjab 140307 India.

⁵Chitkara College of Pharmacy, Chitkara University, Rajpura,Punjab, India.

⁶Department of Pharmacology Chandigarh College of Pharmacy, CGC Landran Mohali, Punjab 140307 India.

 

ABSTRACT:

CVDs remain the uppermost disorder of mankind and the number of cases is unceasingly growing at unaccustomed rates. For instance; Myocardial hypertrophy, Heart failure, sudden cardiac arrest, MI, and so on. TLR plays a vital role in heart diseases and its family member TLR4 possesses a huge role in cardiac hypertrophy signaling. In this review, we compiled the various characteristics of TLR4 involving signal transduction of cardiac hypertrophy, its co-receptors, and ligand’s role in cardiac hypertrophy. A detailed literature search was accomplished using multiple online search engines like Google scholar and Pub med with regards to the available research and review accounts on TLR4 role in Hypertrophic Cardiomyopathy. Activities of Toll-like receptor 4 were selected reporting the significant addition from all the articles. The reviewed reports confirmed the TLR4 role in triggering myocardial hypertrophy.

 

 

 

INTRODUCTION: 

TLR4 causes acute and severe inflammation, and after initiation of immune response is a key PRR.  TLR4 transduction pathway regulation is possibly an effective way of managing the pathophysiology of myocardial hypertrophy due to the implication TLR4 mediated immune response in the management of cardiac hypertrophic remodeling shown in past years evidence.¹

 

Pattern recognition receptors consist of TLRs which identify PAMPs also known as pathogen-associated molecular patterns obtain through several microorganisms, along with, bacteria, viruses, and pathogens. Toll-like receptors also recognize DAMPs (damaged associated molecular patterns. TLR4 is an inflammatory protein and a major TLR family member, which performs a vital function in cardiac hypertrophy and hypertension pathogenesis². TLR4 activation triggers a signaling cascade which in turn activates inflammatory cytokines, which regulate cardiac hypertrophy progression and seditious responses³.

 

Signaling Cascade MOA of Toll Like Receptor 4:

Homo sapiens TLR4, the first-ever characterized mammalian TLRs (single-pass transmembrane protein) after binding to PAMPs or DAMPs (exogenous or endogenous ligands), can initiate an inflammatory response. Initially, TLR4 binds to ligands after forming a complex with its co-receptors. The ligand binds to LBS or lipopolysaccharides mostly studied in PAMP. LPS/LBS complex attaches to CD14– protein catalyzes Lipopolysaccharide transmission by TLR4 into another pre-formed complex and surface receptor MD2⁴. LPS/TLR4/Myeloid D2 response complex triggers inflammatory signaling pathways. TLR4 through two distinct intracellular pathways (MyD88, TRIF) dependent can convey signals. MyD88 triggers NF-Kb and MAPK, due to activating signal transduction through adaptor proteins. Various inflammatory chemokines like TNF-α, IL-1ß, IL-6, and MCP-1 are produced, due to the activation of the signaling pathway that triggers Kb or AP-1⁵. MyD88 regulates Ca2+/CaMK 11 or PI3K/Akt and regulates pro-inflammatory chemokines transcription. TRIF similarly activates transcription factors like MyD88 dependent pathway and triggers the IFN-inducible genes and expression of IFNs⁶.

 

TLR4 Starts a Seditious Reaction in Myocardial hypertrophy:

Pathogenesis of myocardial hypertrophy includes Spontaneous overburden and Neuro-hormonal mechanism. Pressure overload and volume overload are part of Mechanical overload⁷. Neuro-hormonal stimulation develops catecholamine and Angiotensin 11 generation through the sympathetic- adrenomedullary system and RAS respectively, which leads to cardiac hypertrophy and hypertension. The heart is mechanically forced by persistent pressure overload, which releases hypertrophic stimuli—of which only a few are DAMPs—that activate TLR4 and cause inflammation and the innate immune system to respond⁸. TLR4 expression down-regulation has been shown to reduce cardiac hypertrophy and limit the inflammatory response that TLR4 is associated with. Ha, et al. demonstrated the function of TLR4 using the mouse in/Vivo model⁹. They employed AB in both TLR4 deficient and wild-type animals and discovered taking down TLR4 minimize the growth of cell and restores hypertrophic cardiomyopathy. Instead of looking at knockout studies Ehrentraut et, al. studied the pharmacological role of TLR4. Mice treated with eritoran (targets lipid A) with a TLR4 antagonist have a lower LV/BW ratio than mice that were not treated. Pro-inflammatory cytokines and hypertrophic indicators have been attenuated in groups of people using drugs, according to quantitative PCR and ELISA studies¹⁰. Because TLR4 is centrally blocked, mean arterial pressure, the generation of pro-inflammatory mediators, and heart hypertrophy are all inhibited.

 

 

Figure 1. TLR4 signaling pathways: MyD88-dependent and independent downstream signaling. MyD88- dependent signaling produces pro-inflammatory cytokines through IRAK/TRAF6/TAK1 and MAPK an NF-κB activation. MyD88- independent signaling produces type I IFNs through TRIF/TRAM/TBK1 and IRF 3 activation. (Kim et al. Immunity and ageing, 2023)

 

TLR4 Surface Receptor’s Role in Myocardial Hypertrophy:

TLR4 - MD2 complex dimerization turn on the seditious signaling pathway of Toll-like receptor 4. TAC- induced cardiac hypertrophy results in enhanced CD14 expression, which is then further augmented by LPS stimulation¹¹. Han and colleagues' findings made clear that Ang 11 directly interacts with MD2 for the creation of the MD2/TLR4 complex (independent of LPS), which explains why CD14 does not contribute to Ang 11-induced myocardial hypertrophy. MD2 deficiency reduced inflammation, fibrosis, and hypertrophy in ang-11-induced myocardial hypertrophy by disrupting MD2/TLR4 combination; supportingAng-11 activates TLR4 in an MD2- dependent manner¹². Similarly, in HFD (high-fat diet) model, palmitic acid, LDL, and total cholesterol were used to induce the myocardial hypertrophy model, where MD2 blocker L6H21 and MD2 knockout mice alleviated the fibrosis, hypertrophy in the HFD-induced model by decreasing cytokines production. MD2 activates TLR4, is but also included in pressure overload, reperfusion injury, or myocardial ischemia¹³. Myeloid differentiation 1 also called lymphocyte antigen 86 (MD-1 cardiac expression is induced in mice which gives protection against fibrosis and myocardial glycoprotein) which forms a complex with Radioprotective 105 – TLR homolog regulates TLR4 signaling)¹⁴. 2:2 unusual homodimer formation through TLR4-MD2 and RP-105-MD1 cause changes in the TLR4 signaling cascade. RP-105 inhibits the TLR4 signaling pathway and protects against myocardial ischemia-reperfusion its insufficiency heightens ailment in MI mice. MD-1 accessory molecule is necessary for RP105 to express on the cell surface. It has been shown that Human hypertrophy after inhibiting MEK-ERK ½ and NF-kB signaling and in response to pressure overload MD-1 exhibits the opposite type¹⁵. In recent research in HFD- induced obesity, MD1 expression decreased, due to which cardiac injury, left ventricular hypertrophy or electrical remodeling of the atrium occurred¹⁶. These findings suggest that for the prevention and treatment of TLR4- mediated inflammatory diseases, a therapeutic approach of TLR4 co-receptor controlling expression can be used.

 

TLR4 Ligands role in Cardiac Hypertrophy:

It has been described that HMGB1, HSP 70, S100A8/S100A9, or Fibronectin are endogenous molecules from DAMPs, activate inflammatory response through TLR4/MD2 complex interaction¹⁷. Heat Shock Proteins Heat shock proteins, members of molecular chaperones, are known for their involvement in the maturation, refolding, and destruction of proteins¹⁸. These proteins are found in certain locations and some of them are elevated in the presence of stressful stimuli. These proteins are made up of several components such as Heat Shock Protein 60 and HSP70, which are essential TLR4 ligands¹⁹. Heat shock protein 60 is a TLR4 ligand, found on the cardiac myocyte’s surface. TLR4 activation in the immune system is characterized by (NF) Kb nuclear factor activation followed by TNF-activation. HSP60 induces cardiac myocyte apoptosis by activating TLR4 (4). HSP60 (an agonist of TLR4) triggers cardiac hypertrophy and upregulates BNP (brain natriuretic peptide) and α- actin by stimulating the innate immune system and the complement system is also activated²⁰. HSP70 (70-kDa) is found in the cytosol, in the extracellular matrix, or in cell membranes. HSP70 up-regulation survival of cell in endogenous or exogenous challenges. HSP70 human family is made up of 8 unique gene products which are different from expressions or by amino acid sequence^21,22. Three stress activating Isoforms – HSP70 (-1a, -1b,-6) and another 5 that does not respond to pressure – HSP70 (-1t,-2, -5,-9), HSC70. HSP70 are chaperones that control diverse proteins folding through accessory co-chaperones help, which get energy through ATP hydrolysis. HSP72 (also known as HSP70) provides protection in the acute phase of injury. IT binds with S394-phosphorylated HDAC2 and gives protection against phosphatase-dependent dephosphorylation and maintains the HDAC2 activation because HDAC2 (histone deacetylase 2) initiates myocardial hypertrophy^23,24. HDAC2 phosphorylation triggers cardiac hypertrophy which increased the anti- hypertrophic effect possibility through HSP70 interruption^25,26.

 

High Mobility Group Box 1:

HMGB1 triggers innate immunity and stimulates inflammation in cardiac disorders. It exists in the heart cells or in the nucleus and cytoplasm. HMGB1 after attaching to receptors stimulates a signaling cascade and causes cardiovascular disorders and inflammation^{27, 28}. Nuclear HMGB1 translocate into extracellular space and cytoplasm, under viral infection, apoptosis, and hypoxia. Extracellular and cytoplasmic HMGB1 attach to a variety of receptors such as TLR4, RAGE, and TLR2 or trigger different immune cells accumulation and chemokines secretion or cytokines respectively^28-30. Both HMGB1 work together and cause cardiac disorders by damaging cardiac tissue and remodeling^{31, 32}. As a DAMP, HMGB1 triggers non-infectious inflammation and works as an alarm during damaging tissue or immune responses. TLR4 and RAGE interact with extracellular HMGB1 which leads to the induction of adhesive molecules, chemokines, and cytokines production and causes myocardial ischemia and inflammation. Ang 11 and ET-1 are hypertrophic mediators that cause translocation and acetylation of nuclear HMGB1 in NRCM; conversely managing a stable level of HMGB1 in cells prevents myocardial myopathy. Via JAK/STAT signaling CM hypertrophy is mediated by activation through HMGB-mediated IL-6 up-regulation^33,34.

 

FIBRINOGEN:

Fibrinogen is a 340 kDa glycoprotein, synthesized in the liver, and its level during acute inflammation increases by 7mg/ml. It is composed of 2 sets of 3 polypeptide chains – Aα, Bß, and gamma. Appiah et al. give a conclusion that inflammatory response is shown by y’ fibrinogen level and may cause CVD, however, y’ fibrinogen does not independently promote cardiovascular disorders. Fibrinogen-like protein 2 is included in angiogenesis, apoptosis, and inflammatory response^{35, 36}. It has been found that Fgl2 silencing decreases TNF, expression of bcl2, bax, TLR4, and p38 MAPK. FGL2 is an immune coagulant that aids in the development of many cell types. It has been discovered that FGL2 depletion interfered with the growing CMs' typical hypertrophic development and polyploidization^{37, 38}.

 

 

 

Table 1- Exogenous And Endogenous Ligands and Localization of TLRs³⁹

TLRs	Exogenous ligands	Endogenous ligands	Localization	Signaling
TLR1	Triacyl-lipopeptide		Surface of cell	MAL-MyD88-NF- Kb/AP-1IRF5 Pathway
TLR2	Lipoproteins/lipopeptides, peptidoglycan, LTA, lipoarabinomannan, glycosylphop- Hatidylinositolanchors, zymosan, glycolipids, and porins	HSP60, HSP70, Gp96, and unsaturated fatty acids	Surface of cell	MAL-MyD88-NF- Kb/AP-1IRF5 pathway; MAL- MyD88-NF-Kb/AP- pathway
TLR3	dsRNA	mRNA	Intracellular Compartments	PI3K/TRIF-IRF3 Pathway; TRAM- -TRIF-NF-KB Pathway; PI3k/TRIF-RIP1-NF-Kb pathway
TLR4	LPS, RSV protein F, MMTV envelope protein, VSV glycoprotein G, mannan, glucuronoxylomannan, glycosylinositolphospholipids,    and paclitaxel	Biglycan, CD 138, crystalline A chain, β- defensin 2, fibrinogen, fibronectin, heparan sulfate, HMGB1, HSP22–60–70–72, hyaluronan, monosodiumurate crystals, oxPAPC, resistin, surfactant protein A, tenascin-	Surface of cell	MAL-MyD88-NF- κB/AP-1 pathway; TRAM-TRIF-NF- κB/IRF3/IRF7 pathway
TLR5	Flagellin		Surface of cell	MyD88-NF-Kb/IRF5 Pathway
TLR6	Phenol-soluble modulin, diacyl, lipopeptides, LTA, zymosan, oxLDL, amyloid-β fibrils		Surface of cell	Mal-MyD88-NF- κB/AP-1 pathway
TLR7	sRNA, imidazoquinolinone, loxoribine, bropirimine, resiquimod, and imiquimod		Intracellular compartments	MyD88 and endosomal acidification (maturation)-IRF7 pathway; MyD88- NF-κB pathway
TLR8	sRNA, residued		Intracellular compartments	MyD88 and endosomal acidification (maturation)-IRF7 pathway; MyD88- NF-κB pathway
TLR9	Unmethylated CpG DNA, hemozoin	Chromatin-IgG complexes	Intracellular compartments
TLR10		Not known
TLR11	Profilin, pathogenic E. coli		Surface of cell

 

TLR4 Transduction Pathways Associated With Cardiac Hypertrophy:

There are two separate paths taken by TLR4 signals, known as the TLR4/MyD88 pathway and the TLR4/TRIF pathway (11). NF-kB and MAP Kinases signaling are frequent downstream in the MyD88- dependent pathway, but in TLR4/MyD88, PI3K/Akt or Ca2+/CaMK 11 transduction plays a crucial role in harming cardiac tissue^{40, 41}.

 

TLR4/MyD88/NF-kB Signaling Cascade:

An inflammatory response is also initiated by NF-kB, which also encourages the synthesis of genes for pro- inflammatory chemokines. Blocking of NF-kB nuclear translocation can improve myocardial hypertrophy^{42, 43}. While MyD88 over-expression triggers the NF-kB pathway and results in cardiomyocyte mortality in pressure-overload cardiac hypertrophy in vivo, MyD88 inhibition dampens the hypertrophic response^{44, 45}. There is proof that the TLR4/MyD88/NF-kB pathway is connected to hypertension in the brain. In the cardiac hypertrophy model or in hypertension, Ang 11 plays an effector hormone of RAS. Blocking of TLR4 in the brain decrease NF-kB activity that down-regulate inflammatory cytokines. There have been discovered additional mediators linked to the TRIF/MyD88/NF-kB pathway. RBP4 has recently been discovered to be essential in cardiac hypertrophy and failure. Lack of Retinol-Binding Protein restored GLUT4 expression to normal levels in cardiomyocytes and decreased the hypertrophic response^{46, 47}. It has been found that RBP4, TLR4- mediated signaling pathways promote pro- inflammatory cytokines or cardiac hypertrophy and disturb GLUT-4 expression in cardiomyocytes. There is a substantial correlation between TLR4/MyD88/NF-kB and myocardial hypertrophy, according to research.

 

TLR4/MyD88/MAPK Pathway:

MAP kinases are serine-threonine kinases proteins that exhibit an essential role in the pathogenesis of several disorders and coordinate cellular activities e.g., proliferation, survival, and inflammation^{48, 49}. Mitogen-activated protein kinase cascade activated by MyD88. MEK, MAPK14, also known as p38, and other members of the MAPK family that are activated participate in gene transcription or, in the case of MAPK14 and MEK, in the stability of IL6 mRNA. AP-1 or various other transcription factors are activated by activation of MAPKs through TLR4 recruits MyD88 and pro-inflammatory cytokines expression are contributed. Inclined MAPKs in myocardial tissues enhanced cardiac hypertrophy. There have been several studies done to investigate the function of TLR4/MAPK signaling cascade in myocardial hypertrophy. To either directly or indirectly regulate ERK1/2, JNK, and p38 MAPK, pharmacological inhibitors or gene knockout animals are used. TLR4 expression reduced ERK1/2 and p38 MAPK phosphorylation levels and enhanced myocardial hypertrophy in hypertensive rats^{50, 51}. Recent studies have shown that the interaction between MD1 and TLR4 prevents MAPK signaling from starting, suppressing the hypertrophic response. Therefore, MD1 may control the development of myocardial hypertrophy as a novel pharmacological target.

 

TLR4/MyD88/CaMK11 Pathway:

Serine-heroine kinase CaMK11 is vital for managing Ca2+ homeostasis (Yamauchi, 2005). When the Ca2+/ CaM combination attaches to the CaM regulatory domain binding site, CaMKII is stimulated. Thus, successions of autophosphorylations on Thr287 monomers modify their shape, expose the catalytic domain, and enable kinase activity⁵². The phosphorylation of ryanodine (RYR) at site S2814 increases the likelihood that it will open, while the phosphorylation of LTCC at site T17 encourages the development of phospholamban's separation from SERCA2a, hence raising SERCA2a activity^{53, 54}. To put it another way, CaMKII is a protein that is found in the heart and causes arrhythmia. During myocardial dysfunction, CaMKII levels are enhanced.

 

TLR4/TRIF-Dependent Signaling Cascade:

The MyD88-independent pathway, also known as the TRIF-dependent pathway, is a mode of communication for TLR4. Additionally, it is believed to be the main signaling pathway that mediates cardiovascular disorders. The TRIF-dependent pathway has been shown to be a determinant in hypertension and myocardial hypertrophy, in contrast to the MyD88-dependent system^{55, 56}. The fact that in MyD88-deficient mice, the inflammatory response did not diminish but rather increased, accompanied by an increase in TLR4 and TRIF cardiac expression, provides additional proof that MyD88-dependent signaling functions as a negative regulator of the pro-inflammatory pathological response mediated by TRIF in the context of high dose Ang II-induced myocardial hypertrophy. According to a recent study, the TLR4 antagonist LPS-RS lowers the expression of TRIF but not MyD88 in a model of hypoxia-induced LV hypertrophy. These results reveal that TLR4/TRIF pathway is involved in myocardial hypertrophy.^{57, 58}

 

CONCLUSION:

Numerous investigations on TLR4 have been conducted. In the current publication, we present evidence from the literature suggesting TLR4 plays a significant role in both inflammation and cardiac hypertrophy. Additionally, we have gathered several publications that briefly describe the mechanism of action and signal transduction of toll-like receptors in cardiac hypertrophy. In signal transduction, TLR4 possesses a great role in inflammatory response after binding to PAMPs and DAMPs. MyD88 and TRIF are 2 pathways for conveying signals by TLR4. Additionally, a detailed role of TLR4 initiating inflammatory response has been described in the available manuscript, the role of TLR4 co-receptors, TLR4 ligand’s role in cardiac hypertrophy which include briefly idea about heat shock proteins, fibrinogen, etc. Furthermore, signaling pathways such as TLR4/MyD88/NF-KB, MAPK, CaMk11 pathway, and TLR4/TRIF dependent pathway is described. On the contrary, phenotypes of immune cells and more ligand mechanisms which bind TLR4 or HOW TLR4 is activated are yet to answer and knowledge regarding the role of TLR4 signaling is insufficient. It can be predicted that TLR4 will be explored more such as TLR4 inhibitors which can inhibit activation of signaling of TLR4, identifying TLR4 signaling upstream molecules which will be novel. Before TLR4 inhibitors may be fully utilized in clinical settings, new technology to deliver drugs directly to the heart and a lot of extensive investigations are required.

 

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Received on 19.05.2025      Revised on 08.09.2025 Accepted on 27.11.2025      Published on 01.07.2026 Available online from July 04, 2026 Research J. Pharmacy and Technology. 2026;19(7):3401-3407. DOI: 10.52711/0974-360X.2026.00483 © RJPT All right reserved
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