Neurotrophic Factors: Emerging Biology and Therapeutic Applications for Cardiovascular Diseases

Figures

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  Figure 1. The roles of NTFs in CVDs. NTFs have been demonstrated to play a pivotal role in the regulation of cardiac remodeling and cardiac function, achieved through abundant pathophysiologic processes, including angiogenesis, oxidative stress, inflammation, ER stress, apoptosis, mitochondrial dysfunction, autophagy, and cell death. This figure was created in BioRender. Akt, serine/threonine-specific protein kinase; BDNF, brain-derived neurotrophic factor; CNTF, ciliary neurotrophic factor; CDNF, cerebral dopamine neurotrophic factor; CGRP, calcitonin gene-related peptide; Caspase, cysteinyl aspartate specific proteinase; ERK, Extracellular regulated protein kinase; Foxo, forkhead box-O transcription factors; ER, endoplasmic reticulum; IL-1β, interleukin-1β; IL-13, interleukin-13; IL-10, interleukin-10; JAK, Janus kinase; LV, left ventricle; MANF, mesencephalic astrocyte-derived neurotrophic factor; mTOR, mammalian target of rapamycin; NT-3, neurotrophin-3; NF-κB, nuclear factor kappa-B; NGF, nerve growth factor; NOX, NADPH-oxidase; PI3K, phosphatidylinositol 3-kinase; TRPV1, transient receptor potential vanilloid-1; STAT, signal transducer and activator of transcription; TRPC, transient…

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  Figure 2. Exercise activates the regulation of NTFs for cardioprotection. Exercise modulates the secretion of NTFs to confer cardioprotective effects via organ communication, which eventually improves cardiac function and increases myocardial survival by boosting mitochondrial function, regulating cardiomyocyte Ca2+ cycling, promoting angiogenesis, maintaining cardiac bioenergetics and attenuating oxidative stress, inflammation, and apoptosis. This figure was created in BioRender. eNOS, endothelial nitric oxide synthase; HO-1, heme oxygenase 1; NO, nitric oxide; SIRT1, silent mating type information regulation 2 homolog-1; βARs, β-adrenergic receptors; →, invovled; ⇢, uncertain.

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  Figure 3. The roles of small molecule agonists/mimetics in modulating cardiac function. This illustrates that 7,8-DHF and 7,8,3′-THF activate key signaling pathways, including Akt, AMPK, and STAT3 to promote cell survival. Concurrently, they can also inhibit the TGF-β1/Smad2/3 axis, thereby attenuating cardiac fibrosis. This figure was created in BioRender. AMPK, AMP-activated protein kinase; Akt, serine/threonine-specific protein kinase; Bmal1, brain and muscle Arnt-like protein 1; MMP, mitochondrial membrane potential; STAT, signal transducer and activator of transcription; TGF-β1, transforming growth factor-β1; 7,8,3′-THF, 7,8,3′-Trihydroxyflavone; 7,8-DHF, 7,8-Dihydroxyflavone.

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  Figure 4. The overview of NTF-modified stem cell therapeutic strategy for cardiac repair. Several types of stem cells, including embryonic stem cells, hematopoietic stem cells, bone marrow mesenchymal stem cells, and adipose-derived stem cells, are considered as potential candidates for myocardial regeneration. One pivotal step is to introduce NTF genes into cells, which then undergo preclinical trials in animal models before clinical trials to evaluate safety and effectiveness in human patients. This figure was created in BioRender.