Midkine—A novel player in cardiovascular diseases

Abstract

Midkine (MK) is a 13-kDa heparin-binding cytokine and growth factor with anti-apoptotic, pro-angiogenic, pro-inflammatory and anti-infective functions, that enable it to partake in a series of physiological and pathophysiological processes. In the past, research revolving around MK has concentrated on its roles in reproduction and development, tissue protection and repair as well as inflammatory and malignant processes. In the recent few years, MK's implication in a wide scope of cardiovascular diseases has been rigorously investigated. Nonetheless, there is still no broadly accepted consensus on whether MK exerts generally detrimental or favorable effects in cardiovascular diseases. The truth probably resides somewhere in-between and depends on the underlying physiological or pathophysiological condition. It is therefore crucial to thoroughly examine and appraise MK's participation in cardiovascular diseases. In this review, we introduce the MK gene and protein, its multiple receptors and signaling pathways along with its expression in the vascular system and its most substantial functions in cardiovascular biology. Further, we recapitulate the current evidence of MK's expression in cardiovascular diseases, addressing the various sources and modes of MK expression. Moreover, we summarize the most significant implications of MK in cardiovascular diseases with particular emphasis on MK's advantageous and injurious functions, highlighting its ample diagnostic and therapeutic potential. Also, we focus on conflicting roles of MK in a number of cardiovascular diseases and try to provide some clarity and guidance to MK's multifaceted roles. In summary, we aim to pave the way for MK-based diagnostics and therapies that could present promising tools in the diagnosis and treatment of cardiovascular diseases.

Evaluation of Midkine Protein in a Sample of Iraqi Patients with Newly Diagnosed Hypothyroidism and Subclinical Hypothyroidism

“…and from complications for hypothyroidism-related cardiovascular disease, MK has been associated with a number of cardiovascular diseases, and many research investigations on cardiovascular diseases have found elevated MK expression. (Majaj and Weckbach 2022).Estimating serum electrolyte levels may be essential to controlling hypothyroid patients; it should be taken into account as it can assist in preventing future issues (Koner and Chaudhuri 2022). Statistical analysis did not show a significant difference in sodium levels among the groups, This result matched past studies (Wiwanitkit 2020).…”

Midkine (MDK) in Hepatocellular Carcinoma: More than a Biomarker

“…It is composed of two domains, each including three antiparallel β-strands and various heparin-binding consensus sites [14], which enable its binding to heparan sulfate and chondroitin sulfate and the formation of a molecular complex with proteoglycans [18]. Importantly, MDK binding to sulfated glycosaminoglycans (GAGs) leads to interactions with several key receptors, including protein-tyrosine phosphatase-ζ (PTP-ζ), syndecans, low-density lipoprotein receptor-related protein (LRP), α4β1 and α6β1 integrins, and neurogenic locus notch homolog protein 2 (Notch-2), while it has also been reported to phosphorylate the cell-matrix adhesion proteins paxillin and focal adhesion kinase (FAK) [19] (Figure 1). Such interactions prompt, in turn, the activation of major pro-survival signaling pathways, including Src family kinase, phosphoinositide 3 kinase (PI3K), mitogen-activated protein kinase (MAPK), and nuclear factor kappa B (NF-κΒ), which in turn promote various cellular functions, such as cell proliferation, survival, adhesion, migration, and angiogenesis (Figure 2) [20,21].…”

Spatiotemporal Transcriptomes of Pig Hearts Reveal Midkine-Mediated Vascularization in a Chronic Myocardial Infarcted Model

“…MDK was shown to be associated with cardiac pathology and angiogenesis 44 . It has been demonstrated that MDK is both necessary and sufficient to promote endothelial growth factor A cell proliferation in growing collaterals 45 .…”