Review
Towards the understanding of the local hematopoietic bone marrow renin-angiotensin system

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Abstract

The classical view of the renin-angiotensin system (RAS) as a circulating endocrine system has evolved to organ- and tissue-based systems that perform paracrine/autocrine functions. Angiotensin II (Ang II), the dominant effector peptide of the RAS, regulates cellular growth in a wide variety of tissues in (patho)biological states. In 1996, we hypothesized that there exists a locally active RAS in the bone marrow affecting the growth, production, proliferation and differentiation of hematopoietic cells. Evidences supporting this hypothesis are growing. Ang II, through interacting with Ang II type 1 (AT1) receptor stimulates erythroid differentiation. This stimulatory effect of Ang II on erythropoiesis was completely abolished by a specific AT1 receptor antagonist, losartan. AT1a receptors are present on human CD34+ hematopoietic stem cells. Ang II increases hematopoietic progenitor cell proliferation and this effect was also blocked by losartan. Angiotensin-converting enzyme (ACE) is involved in enhancing the recruitment of primitive stem cells into S-phase in hematopoietic bone marrow by degrading tetrapeptide AcSDKP. ACE inhibitors modified the circulating hematopoietic progenitors in healthy subjects. RAS may also affect pathological/neoplastic hematopoiesis. Renin has been isolated from leukemic blast cells. Higher bone marrow ACE levels in acute leukemic patients suggested that ACE is produced at higher quantities in the leukemic bone marrow. In this review, the ‘State of the Art’ of the local bone marrow RAS is summarized. A local RAS in the bone marrow can mediate, in an autocrine/paracrine fashion, some of the principal steps of hematopoietic cell production. To show a causal link between the components of RAS and the other regulatory hematopoietic growth factors is not only an academic curiosity. Elucidation of such a local bone marrow system may offer novel therapeutic approaches in pathologic/neoplastic conditions.

Introduction

After the introduction of first angiotensin-converting enzyme (ACE) inhibitor, captopril, into the clinical practice, a marked progress occurred in the treatment of essential hypertension. Substantial studies led to development of new ACE inhibitors and angiotensin (Ang) II receptor antagonist and widespread use of those agents in a variety of indications beyond hypertension. However, several untoward effects including angioedema, rash and cough observed during ACE inhibitor therapy. Several observations also revealed that ACE inhibitors were associated with anemia and leukopenia (Nomura et al., 1996, Nomura et al., 1996; Vasku et al., 1998). The suppressive action of ACE inhibitors on normal erythropoiesis was demonstrated in hypertensive patients with kidney diseases suggesting that ACE inhibitors have disturbing effects on hematopoiesis (Nomura et al., 1996, Nomura et al., 1996, Rell et al., 1994). In the postrenal transplant erythrocytosis, ACE inhibitors and AT1 receptor antagonist (losartan) have effectively reduced hematocrit levels (Rell et al., 1994; Conlon, Smith, Butterly, & Brennan, 1996). Moreover, renin and aldosterone levels were threefold greater in chronic obstructive pulmonary disease (COPD) patients with secondary erythrocytosis than in CPOD patients with normal hematocrit values, indicating that activation of renin-angiotensin system (RAS) is associated with the development of erythrocytosis (Vlahakos et al., 1999). Regarding the effects of Ang II as a locally active growth factor in several tissues, we proposed the hypothesis for the presence of a local RAS in the bone marrow in 1996 (Haznedaroglu, Tuncer, & Gursoy, 1996). According to this hypothesis, there exists a locally active, intrinsic RAS in the bone marrow that might functionally affect the growth of hematopoietic colonies, cellular production, proliferation, and differentiation in physiological and pathological states, as in other tissues (Huckle & Earp, 1994). Since then, a number of investigations have been reported regarding the interactions of RAS and hematopoiesis (Hajek et al., 1999; Rodgers, Xiong, Steer, & DiZerega, 2000). The aim of this review is to briefly summarize the scientific background and the ‘State of the Art’ of the local bone marrow RAS.

Section snippets

Scientific background of the local hematopoietic bone marrow RAS

The historical view of RAS as the solely circulating endocrine system has now been expanded to embrace a broader concept that includes organ and tissue-based systems that perform paracrine and autocrine functions. Many studies have provided evidence for the locally operating RASs particularly in the cardiac, vascular and renal tissues (Danser et al., 1999, Dostal and Baker, 1999, Fischer et al., 1998, Holtz and Goetz, 1994, Iwai et al., 1988, Kifor and Dzau, 1987, Ruzicka and Leenen, 1997, So

RAS elements and hematopoietic system: initial clues

Several blood cells have been shown to carry essential RAS elements. Renin is expressed in circulating rat macrophage/monocyte cells (Iwai, Inagami, Ohmichi, & Kinoshita, 1996). Rat leukocytes in the bloodstream express the angiotensinogen gene, synthesize and release angiotensinogen with the capability to generate angiotensin (Gomez et al., 1993), although angiotensin generation could not be proven in human leukocytes (Davis, Liyou, & Johnson, 1998). On the other hand, angiotensinogen was

Cumulating evidences for the local hematopoietic bone marrow RAS

Evidence is now really accumulating to indicate the existence of a local RAS in the bone marrow, which may be operative in normal and malignant hematopoiesis with sensitivity to pharmacological maneuvers (Table 1). Ang II, through interacting with AT1 receptor enhances erythroid differentiation in the bone marrow. Ang II-stimulated erythroid progenitors formed significantly higher numbers of burst-forming unit-erythroid (BFU-E) colonies in normal human erythropoiesis. This stimulatory effect of

The RAS elements in pathological hematopoiesis

Furthermore, there is preliminary evidence that RAS may affect pathological/neoplastic hematopoiesis in the bone marrow. A renin-like enzyme activity converting angiotensinogen to angiotensin I was determined in leukemic blast cells (Wulf et al., 1996). Afterwards, a specific immunoreactive renin-like peptide of 47 kDa was isolated from AML blast cells (Wulf et al., 1998). In view of the emerging concepts on local RAS in different organs, this data claim attention to the role of renin-like

An analogical approach to the hematopoietic bone marrow RAS among other local RASs

Cardiac RAS is an analogical model for the hematopoietic bone marrow RAS (Haznedaroglu et al., 1996; Lijnen and Petrov, 1999a, Lijnen and Petrov, 1999c). Local myocardial RAS plays an important role in cardiac hypertrophy and remodeling via the activation of protein tyrosine kinases that involved in cell differentiation and proliferation (Akiyama et al., 1999). Locally produced Ang II may stimulate myocyte hypertrophy, ventricular remodeling, ameliorate myocyte contractile performance, and

Perspectives for the future: fill in the blanks of hematopoietic RAS

The identification of RAS components and Ang II receptors in the hematopoietic bone marrow may suggest the existence of an autocrine/paracrine system that has effects independent of Ang II derived from the circulatory system (Rodgers et al., 2000). As brilliantly reviewed for the local cardiac RAS by Dostal and Baker ‘to be functional, a local RAS should produce sufficient amounts of the autocrine and/or paracrine factor to elicit biological responses, contain the final effector (Ang II

Perspectives for the future: the local RAS-stem cell plasticity puzzle and research horizons

Taken together, some previously mentioned findings seem to be consistent with the locally active RAS in the bone marrow. Nevertheless, our knowledge about the local hematopoietic bone marrow RAS is still in “neonatal period”. Current perspective of this local system opens up new horizons for research regarding the pathogenesis of blood disorders.

Multipotent cardiac stem cells may renew the myocardium (Anversa & Nadal-Ginard, 2002). Transplantation of hematopoietic stem cells are capable of

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