Signaling cascades in the failing heart and emerging therapeutic strategies

Abstract

Chronic heart failure is the end stage of cardiac diseases. With a high prevalence and a high mortality rate worldwide, chronic heart failure is one of the heaviest health-related burdens. In addition to the standard neurohormonal blockade therapy, several medications have been developed for chronic heart failure treatment, but the population-wide improvement in chronic heart failure prognosis over time has been modest, and novel therapies are still needed. Mechanistic discovery and technical innovation are powerful driving forces for therapeutic development. On the one hand, the past decades have witnessed great progress in understanding the mechanism of chronic heart failure. It is now known that chronic heart failure is not only a matter involving cardiomyocytes. Instead, chronic heart failure involves numerous signaling pathways in noncardiomyocytes, including fibroblasts, immune cells, vascular cells, and lymphatic endothelial cells, and crosstalk among these cells. The complex regulatory network includes protein-protein, protein-RNA, and RNA-RNA interactions. These achievements in mechanistic studies provide novel insights for future therapeutic targets. On the other hand, with the development of modern biological techniques, targeting a protein pharmacologically is no longer the sole option for treating chronic heart failure. Gene therapy can directly manipulate the expression level of genes; gene editing techniques provide hope for curing hereditary cardiomyopathy; cell therapy aims to replace dysfunctional cardiomyocytes; and xenotransplantation may solve the problem of donor heart shortages. In this paper, we reviewed these two aspects in the field of failing heart signaling cascades and emerging therapeutic strategies based on modern biological techniques.

Fig. 1

Functions of different cell types in a failing heart. Heart failure is a complex process that involves multiple cell types in the heart. Under stress, cardiomyocytes undergo either pathological hypertrophy or cell death. Hypertrophy led to cardiomyocyte dysfunction, while non-programmed or programmed cell death led to cardiomyocyte loss. Cardiac fibrosis is another form of cardiac remodeling. It mainly involves fibroblast activation and conversion to myofibroblast. Various immune cells also contribute to heart failure. These cells infiltrate the injured myocardium, secret cytokines, and cleared unwanted material to regulate inflammation, regeneration, and function of other cell types in the failing heart. Both vascular endothelial cells (VECs) and lymphatic endothelial cells (LECs) regulate cardiac function. VECs affect neighboring cardiac cells by paracrine factors. LECs regulate cardiac regeneration after infarction by maintaining fluid balance, promoting immune cell clearance, and also secreting paracrine factors

Fig. 2

RNA related mechanism of cardiac hypertrophy. Recent studies on RNA creates a novel regulatory network for cardiac hypertrophy. (I) Long non-coding RNAs (lncRNAs) are molecularly multi-functional. They can physically interact with and modulate function of cytoplasmic protein, chromatin remodeling factors, and transcription factors. (II) MicroRNAs (miRNAs) target mRNA and suppressed its expression. Circular RNAs (circRNAs) are also multifunctional, but cardiac hypertrophy related researches mainly focuses on their role as miRNA sponges. (III) RNA modification further adds to the complexity of the regulatory network. N6-methyladenosine (m6A) alters the function of mRNA. Modulating m6A “writer” or “eraser” can affect the development of cardiac remodeling. Oxidative stress creates 8-oxoguanine modification on miR-1, which leads to its target mismatch and triggers hypertrophic response. miRNA: microRNA; circRNA: circular RNA; ZFAS1: Zinc finger antisense 1; PRC2: polycomb repressor complex 2; Chaer: cardiac-hypertrophy-associated epigenetic regulator; SERCA2a: sarco/endoplasmic reticulum Ca2+-ATPase 2a; CPhar: cardiac physiological hypertrophy-associated regulator; TF: transcription factor; RISC: RNA Induced Silencing Complex; HRCR: heart-related circRNA; ROS: reactive oxygen species; WTAP: Wilms’ tumor 1-associating protein; METTL3: methyltransferase like 3; METTL14: methyltransferase like 14; m6A: N6-methyladenosine; FTO: fat mass and obesity associated gene; PE: Phenylephrine; ISO: isoprenaline

Fig. 3

Non-programmed and programmed cardiomyocyte death in failing heart. Cardiomyocyte death contribute to loss of myocardium, especially after ischemia injury. Different types of programmed cell death are controlled by their specific signaling pathway. Modulating programmed cell death by targeting their signaling pathway can attenuate cardiac dysfunction after ischemia injury. BAX: BCL-2-associated X protein; BAK: BCL2-antagonist/killer 1; cty C: Cytochrome C; FADD: Fas associated death domain; FasL: Fas ligand; TNF-α: tumor necrosis factor α; TRAIL: TNF-related apoptosis inducing ligand; IAP, Inhibitor of apoptosis; ARC: Apoptosis repressor with caspase recruitment domain; mPTP: mitochondrial permeability transition pore; TNFR: TNF receptor; TRADD: TNFR1-associated death domain; RIPK1: serine/threonine kinases receptor interacting protein kinase 1; MLKL: mixed lineage kinase-like domain; DAMPs: damage-associated molecular patterns; GSDMD: gasdermin D; PNS: perinuclear space; Atg5: Autophagy related 5; Atg3: Autophagy related 3; Tfr: transferrin receptor; TTP: tristetraprolin; GPX4: glutathione peroxidase 4; GSH: glutathione

Fig. 4

Emerging therapeutic strategies to treat failing hearts. Gene therapy via various vectors enables direct manipulation of gene expression. Cell therapy is aimed at replacing the lost functional cardiomyocytes either exogenously or endogenously. Chimeric antigen receptor (CAR) T cell therapy is also proposed to ameliorate cardiac fibrosis and improve cardiac function. Xenotransplantation technique makes pig-to-human heart transplantation possible by overcoming multiple cross-species barriers. Clustered regularly interspaced short palindromic repeats CRISPR)/CRISPR-associated 9 (Cas9) based gene editing has the potential for curing inherited cardiomyopathy in the future. CDK: cyclin-dependent kinase; GTM(H): Gata4, Mef2c, and Tbx5 (Hand2); iPSC: induced pluripotent stem cell; hESC: human embryonic stem cell; CAR T-cell: Chimeric Antigen Receptor T-Cell; sgRNA: small guide RNA; VEGF: vascular endothelial growth factor; FGF4: fibroblast growth factor 4; ASO: antisense oligonucleotide; SERCA: sarco/endoplasmic reticulum Ca2+−ATPase

Fig. 5

Summary of therapeutic strategies based on gene therapy for failing hearts. Early attempts were plasmid and adenovirus based. These reagents are usually locally delivered by intracoronary infusion or intramyocardial injection. The overexpressed genes encode secretory protein related to angiogenesis and tissue repair. In one trial, the putative protective adenylyl cyclase type 6 (AC6) was overexpressed. Recent gene therapy trials adopt adeno-associated virus (AAV). A series of clinical trials are designed to overexpress sarco/endoplasmic reticulum Ca²⁺-ATPase 2a (SERCA2a) in cardiomyocytes to improve Ca²⁺ handling in heart failure. Modified RNAs represent a novel approach to target specific genes. It’s normally systemically delivered. Although there hasn’t been any clinical trial testing RNA therapy for failing heart, preclinical studies using antisense oligonucleotide (ASO) against phospholamban (PLN) showed promising results. AAV: Adeno-associated virus; ASO: antisense oligonucleotide; FGF4: fibroblast growth factor 4; VEGF: vascular endothelial growth factor; SDF-1: stromal cell derived factor-1; SERCA: sarco/endoplasmic reticulum Ca2+-ATPase; PLN: phospholamban; AC6: Adenylyl cyclase type 6

Fig. 6

Summary of therapeutic strategies based on cell therapy for failing hearts. The earliest attempt is myoblast transplantation to the injured heart. However, these cells don’t form connection with neighboring cardiomyocytes. Transplantation of bone marrow derived mesenchymal stem cell (BMSC) shows modest benefit, which is mediated by paracrine factors secreted by BMSC instead of transdifferentiation into cardiomyocytes. Transplantation of inducible pluripotent stem cell derived cardiomyocytes (iPSC-CM) or embryonic stem cell derived cardiomyocytes (ESC-CM) successfully achieve electromechanical coupling between the transplanted and in situ cardiomyocytes, but these therapies have the shortcomings of immune rejection, arrythymogenicity, and teratogenicity. In vivo reprograming tries to induce fibroblast-to-cardiomyocyte transdifferentiation or cardiomyocyte proliferation by gene manipulation to compensate for cardiomyocyte loss. Chimeric antigen receptor (CAR) T cell therapy targeting activated fibroblast has been just proposed by a proof-of-concept study. These CAR T cells can be induced by injection of modified RNA loaded in T cell directed lipid nanoparticles. LNP: lipid nanoparticle; FAP: fibroblast activation protein; iPSC: induced pluripotent stem cell; ESC: embryonic stem cell; MSC: mesenchymal stem cell