Dysfunctional cardiomyocyte signalling and heart disease

Abstract

Cardiomyocyte signalling pathways are central to maintaining the structural and functional integrity of the heart. Dysregulation of these pathways contributes to the onset and progression of heart diseases, including heart failure, arrhythmias and cardiomyopathies. This review focuses on very recent work on dysfunctional cardiomyocyte signalling and its role in the pathophysiology of heart disease. We discuss key pathways, including immune signalling within cardiomyocytes, signalling associated with microtubule dysfunction, Hippo-yes-associated protein signalling and adenosine monophosphate-activated protein kinase signalling, highlighting how aberrations in their regulation lead to impaired cardiomyocyte functions and pinpointing the potential therapeutic opportunities in these pathways. This review underscores the complexity of cardiomyocyte signalling networks and emphasises the need for further dissecting signalling pathways to prevent cardiomyocyte dysfunction.

Figure 1. Molecular pathways involved in inflammatory response in cardiomyocytes.

In response to stress or injury, signalling pathways involving pattern recognition receptors (PPRs) play key roles in mediating innate immune responses in cardiomyocytes. PPRs in response to DAMPs (damage recognition) or PAMPs (pathogen recognition) can lead to activation of the inflammatory pathways. PPRs include transmembrane receptors (e.g. TLRs or IL-Rs) or cytosolic receptors (e.g. NLRP3 or AIM2). Activation through TLR signalling cascades or cGAS-STING activation leads to transcriptional changes in multiple pro-inflammatory cytokines (e.g. TNFα, IL-1β, IL-18, type I IFN). Activation of IL-Rs can be triggered by interleukins, which can bind to the receptor on the cardiomyocyte cell surface and activate JAK/STAT to induce the production of multiple inflammatory cytokines (IL-6, IL-1β and IL-33). Activation of NLRP3 or AIM2 inflammasome results in cleavage of proinflammatory cytokines (IL-18, IL-1β) and GSDMD, leading to the formation of GSDMD pores on the membrane. Black dotted lines represent potential pathway interactions. AIM2, absent in melanoma 2; C-GSDMD, cleaved C-terminal gasdermin D; CASP11, Capase-11; cGAMP, cyclic guanosine monophosphate; cGAS, cyclic GMP-AMP synthase; DAMPs, damage-associated molecular patterns; ER, endoplasmic reticulum; GP130, glycoprotein 130; GSDMD, gasdermin D; IFN, Interferon; IL-11, Interleukin-11; IL-11R, Interleukin-11 receptor; IL-1β, Interleukin 1 beta; IL-18, Interleukin-18; IL-33, Interleukin-33; IL-6, Interleukin-6; IRF1, interferon regulatory factor 1; IRF3, interferon regulatory factor 3; JAK, Janus Kinase; mtDNA, mitochondrial DNA; MYD88, myeloid differentiation primary response 88; N-GSDMD, cleaved N-terminal gasdermin D; Na+, sodium; NF-κB, nuclear factor kappa B; NLRP3, NLR family pyrin domain containing 3; P, phosphate; PAMPs, pathogen-associated molecular patterns; ROS, reactive oxygen species; STAT3, signal transducer and activator of transcription 3; STING, stimulator of interferon genes; TLR, toll-like receptors; TNF-α, tumour necrosis factor-alpha.