Midkine's Role in Cardiac Pathology

Abstract

Midkine (MDK) is a heparin-binding growth factor that is normally expressed in mid-gestational development mediating mesenchymal and epithelial interactions. As organisms age, expression of MDK diminishes; however, in adults, MDK expression is associated with acute and chronic pathologic conditions such as myocardial infarction and heart failure (HF). The role of MDK is not clear in cardiovascular disease and currently there is no consensus if it plays a beneficial or detrimental role in HF. The lack of clarity in the literature is exacerbated by differing roles that circulating and myocardial MDK play in signaling pathways in cardiomyocytes (some of which have yet to be elucidated). Of particular interest, serum MDK is elevated in adults with chronic heart failure and higher circulating MDK is associated with worse cardiac function. In addition, pediatric HF patients have higher levels of myocardial MDK. This review focuses on what is known about the effect of exogenous versus myocardial MDK in various cardiac disease models in an effort to better clarify the role of midkine in HF.

Keywords: cardiac pathology; heart failure; midkine.

Figure 1

Data adapted from Kitahara et al. (2010) [33]. Serum midkine (MDK) levels in adult control and heart failure (HF) patients. (A) Serum MDK levels are significantly higher in adult HF patients when compared to healthy controls. Data extrapolated from Figure 1 in Kitahara et al. (2010). Control n = 60; HF n = 216 p < 0.0001; (B) Patients who had cardiac events (classified as sudden cardiac death, death due to HF, and HF requiring readmission). Data graphed based on results stated in Kitahara et al. (2010). Patients with no cardiac events n = 142; Patients who had cardiac events n = 74 p < 0.001.

Figure 2

Data adapted from Tatman et al. (2017) [57]. Pediatric MDK mRNA expression in LV from non-failing (NF) and failing hearts (HF). (A) MDK mRNA is upregulated in left ventricle (LV) from pediatric HF patients when compared to age-matched NF controls. NF n = 21; HF n = 36; p < 0.0001; (B) MDK expression is higher in the hearts of younger patients regardless of pathology. R² = 0.135; p = 0.005.

Figure 3

Summary of what is known about levels of circulating and myocardial MDK in normal hearts and several cardiac pathologies and how these factors affect cardiac outcomes.