The Cardiovascular Effects of Midkine

Midkine is a heparin-binding growth factor with close structural and functional similarity to Pleiotrophin. Both of these proteins are involved in nervous system development as well as inflammation and the response to ischemia. Midkine and Pleiotrophin are upregulated in many cancers where they promote multiple aspects of tumor growth.1 Conversely, Midkine is also known to block VEGF-induced proliferation of vascular endothelial cells providing an anti-tumor effect.2 Additional functions for Midkine in the cardiovascular system have recently been described that expand its range of impact.

The Renin-Angiotensin System (RAS) is critically important for maintaining the volume and electrolyte balance of the blood. It is initiated by secretion of the protease Renin from renal juxtaglomerular cells. Renin cleaves Angiotensinogen to release the peptide Angiotensin I (Ang I); Ang I is subsequently trimmed by Angiotensin I-converting enzyme (ACE) to produce Angiotensin II (Ang II). Ang II signaling through the AT1 receptor induces a rise in blood pressure via vaso­constriction, and increases heart contractility, aldoster­one release, and sodium retention in the kidney.

Midkine contributes to the activation of the RAS. In an experimental model known as 5/6 nephrectomy, renal failure is simulated by removal of one kidney and infarction of 2/3 of the second kidney. This triggers activation of the RAS in lung and brain tissue resulting in systemic hypertension.3, 4 Circulating levels of Midkine rise due to increased production in the lung and remnant kidney vascular epithelium, and this plays an integral role in the hypertensive response.3 Midkine expression may be induced by oxidative stress since 5/6 nephrectomy also stimulates the production of NADPH oxidase-1, -2, and -4 in the lung leading to the presence of more reactive oxygen species.3 In Midkine-deficient mice that undergo 5/6 nephrectomy, ACE induction in the lung and the hypertensive response are absent, and subcutaneous administration of Midkine restores both.3 Knockout of Midkine (in the absence of renal failure) modulates the expression of several RAS components in the aorta as well.5

Dual Actions of Midkine on the Cardiovascular System.
View Larger Image 		Dual Actions of Midkine on the Cardiovascular System. Midkine can have either deleterious or protective effects on the cardiovascular system. Loss of renal function induces Midkine-dependent upregulation of ACE in the lung, which promotes systemic hypertension. In contrast, Midkine is also upregulated in ischemic heart tissue where it slows cardiac remodeling and promotes the recovery of heart function. While Midkine promotes Ang II production in both situations, the difference in the responses may be determined by whether Ang II subsequently binds to the AT1 or AT2 receptor.

Midkine also assists in tissue recovery from myocardial infarction (MI) by limiting the progression of cardiac remodeling. Remodeling, which ultimately results in heart failure, is characterized by a loss of functional muscle mass in the infarcted area, cardiomyocyte (CM) hypertrophy in the noninfarcted area, and tissue fibrosis due to increased collagen deposition.6 Midkine expression is transiently induced in the heart following MI, preferentially by CM bordering the infarcted region.7, 8, 9 Exogenous Midkine induces a number of favorable local responses that are otherwise absent in Midkine-deficient animals.7, 8, 9 These include increases in the amount of viable cardiac muscle and angiogenesis in the infarcted area, and decreases in ischemic cell apoptosis, CM hypertrophy, and collagen deposition. These effects improve heart function and survival.7, 8 Pleiotrophin is also upregulat­ed in the heart following myocardial infarction, although in contrast to Midkine, it induces CM apoptosis in vitro.10

Elevated blood pressure is generally considered to be a risk factor for myocardial infarction. It is therefore intriguing how Midkine can contribute to the hypertensive response in renal failure, and at the same time, play a protective role in preventing heart failure. An explanation may lie in the involvement of distinct Ang II receptors. The AT2 receptor is primarily expressed during development, but is upregulated in injured heart tissue. AT2 appears to mediate the cardioprotective functions of Ang II, while AT1 carries out most of the hypertension-related actions of Ang II.11 Midkine is required for Ang II production in both settings, with the opposing outcomes potentially being due to Ang II function rather than Midkine itself.

References

  1. Kadomatsu K. & T. Muramatsu (2004) Cancer Lett. 204:127.
  2. van der Horst, E.H. et al. (2008) Neoplasia 10:340.
  3. Hobo, A. et al. (2009) J. Clin. Invest. 119:1616.
  4. Nishimura, M. et al. (2007) Acta Physiol. 189:369.
  5. Ezquerra, L. et al. (2005) Biochem. Biophys. Res. Commun. 333:636.
  6. Takano, H. et al. (2003) Internal Med. 42:465.
  7. Fukui, S. et al. (2008) Ann. Thorac. Surg. 85:562.
  8. Takenaka, H. et al. (2009) Am. J. Physiol. Heart Circ. Physiol. 296:H462.
  9. Horiba, M. et al. (2006) Circulation 114:1713.
  10. Li, J. et al. (2007) J. Biol. Chem. 282:34984.
  11. Levy, B.I. (2005) Am. J. Hypertens. 18:134S.

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