Abstract
Ischemic insults to the heart and brain, i.e., myocardial and cerebral infarction, respectively, are amongst the leading causes of death worldwide. While there are therapeutic options to allow reperfusion of ischemic myocardial and brain tissue by reopening obstructed vessels, mitigating primary tissue damage, post-infarction inflammation and tissue remodeling can lead to secondary tissue damage. Similarly, ischemia in retinal tissue is the driving force in the progression of neovascular eye diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD), which eventually lead to functional blindness, if left untreated. Intriguingly, the easily observable retinal blood vessels can be used as a window to the heart and brain to allow judgement of microvascular damages in diseases such as diabetes or hypertension. The complex neuronal and endocrine interactions between heart, retina and brain have also been appreciated in myocardial infarction, ischemic stroke, and retinal diseases. To describe the intimate relationship between the individual tissues, we use the terms heart-brain and brain-retina axis in this review and focus on the role of transforming growth factor β (TGFβ) and neurotrophins in regulation of these axes under physiologic and pathologic conditions. Moreover, we particularly discuss their roles in inflammation and repair following ischemic/neovascular insults. As there is evidence that TGFβ signaling has the potential to regulate expression of neurotrophins, it is tempting to speculate, and is discussed here, that cross-talk between TGFβ and neurotrophin signaling protects cells from harmful and/or damaging events in the heart, retina, and brain.
Highlights
Cardiovascular diseases such as myocardial infarction and ischemic stroke are prevailing causes of death worldwide [1,2,3]
Given the fact that transforming growth factor β (TGFβ) signaling has the potential to regulate neurotrophins (Figure 1B–D) [42,55], it is tempting to speculate that these signaling pathways cooperate with the overall aim of protecting the tissue from harmful events such as Myocardial Infarction (MI)
Subsequent to myocardial infarction, mechano- and chemo-sensitive information is transmitted through cardiac afferent fibers to the brain, which reacts by releasing BDNF into the blood stream—a scenario that is designated as the ‘heart-brain axis’ (Figure 6)
Summary
Cardiovascular diseases such as myocardial infarction and ischemic stroke are prevailing causes of death worldwide [1,2,3]. Neurotrophins and transforming growth factor β (TGFβ) family ligands might constitute regulators along this axis as they are upregulated following ischemic insults in the heart, retina, and brain [6,9,10,11,12,13,14,15,16]. NGF = nerve growth factor, BDNF = brain-derived neurotrophic factor, NT-3 = neurotrophin 3, proNT = pro Neurotrophin, mNT = mature neurotrophin, TGFβ = transforming growth factor β, Trk A–C = tropomyosin receptor kinase A–C, p75 = p75 neurotrophin receptor, TGFβRI/II = transforming growth factor beta receptor 1/2, PLCy = phospholipase C gamma, PKC = protein kinase C, MAPK = mitogen-activated protein kinase, TFs = transcription factors, PI3-K = phosphoinositide 3-kinase, NF-kB = nuclear factor kappa-light-chain-enhancer of activated B cells, JNK = c-Jun N-terminal kinase, GCL = ganglion cell layer, INL = inner nuclear layer, ONL = outer nuclear layer
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