Midkine gene transfer after myocardial infarction in rats prevents remodelling and ameliorates cardiac dysfunction

Abstract

Overexpression of MK prevents LV remodelling and ameliorates LV dysfunction by anti-apoptotic and pro-angiogenic effects. MK gene transfer may provide a new therapeutic modality in ischemic cardiomyopathy and ischemic heart failure.

Functional Receptors and Intracellular Signal Pathways of Midkine (MK) and Pleiotrophin (PTN)

“…13) In addition to receptor ALK, MK and PTN also activate extracellular signal-regulated kinase (ERK1/2) and PI3K/AKT pathways through receptor RPTPζ on osteoblast-like cells 88) and through both ανβ3 and RPTPζ on HUVEC. 54) In the presence of MK, the MAPK and PI3K/AKT pathways participate in injured tissues recovery process, like the recovery of ischemic myocardial injury, [23][24][25][26][27] cartilage trauma [89][90][91] and amphetamine-induced neurotoxicity. 92) MAPK and PI3K/AKT pathways also take part in the proliferation and self-renewal of stem cells, like embryonic stem cells (ES) 20) and hematopoietic stem cell (HSC) after stimulation by PTN.…”

“…At present, anti-cancer drugs targeting MK and PTN and their receptors or intracellular pathways are being developed [101][102][103][104] ; Targeting MK and PTN signaling pathways for curing drug addiction and neurodegenerative disorders also be discussed by Herradon group. 105) Furthermore, more and more research support that MK and PTN not only have potential therapy for ischemic injury of heart and brain, [23][24][25][26][27][28] Alzheimer's disease, 29) hematopoiesis of bone marrow, 21,22) bone and muscle injury, 31) and even human immunodeficiency virus (HIV) infection 69) but also play an important role in tissue regeneration for adult body. 14) So, in the future, clarification of the specific receptor and intracellular pathways of MK and PTN on different kinds of diseases should be basic for MK and PTN related new drug development.…”

“…19) At present, the involvement of MK and PTN in stem cell proliferation and renewal [20][21][22] further highlight their potential as regenerative therapeutics. For example, MK has been demonstrated to promote the recovery of ischemic injury in the heart and brain, [23][24][25][26][27][28] attenuate the deposition of amyloid β-peptide plaques and progression of Alzheimer's disease, 29) facilitate liver regeneration 30) as well as aid in the repair of bone fracture and muscle injury. 31) PTN has also been shown to promote hematopoiesis of bone marrow.…”

Midkine Deteriorates Cardiac Remodeling via Epidermal Growth Factor Receptor Signaling in Chronic Kidney Disease

“…[12][13][14] Midkine is a 13-kDa heparin-binding growth factor that plays diverse physiological roles such as promoting the survival of embryonic neurons and the migration of inflammatory cells. [15][16][17] Midkine is expressed during various pathological conditions such as cancer, renal failure, 18,19 and cardiovascular diseases, [20][21][22] after which it is released into the systemic circulation. 19,23 Midkine secreted from the kidney and lungs might be associated with cardiorenal interactions, but the precise mechanism by which midkine induces cardiac remodeling remains unclear.…”

The Therapeutic Effect of rhMK on Osteoarthritis in Mice, Induced by Destabilization of the Medial Meniscus

“…2) Midkine (MK) is a heparin-binding growth factor, whose another family member is pleiotrophin (PTN). MK and PTN are known for having multi-biological functions, involving nerves 6) and skeletal 7) system development, injured tissue repair (e.g., ischemic myocardial [8][9][10] and brain 11,12) injury, bone fracture 13) ) and regeneration (e.g., liver, 14) skeletal muscle 15) and hematopoietic stem cells 16) ), immune regulation, 17) inflammation 18,19) and tumorigenesis. [20][21][22] MK and PTN not only play an important role in nervous system formation at the embryo stage 6) but also maintain its functions at the adult stage by protecting the injured neuron from apoptosis, preventing degradation of the peripheral and central nerves and promoting the regeneration and new synapses formation of the neuron.…”