Natriuretic Peptide System Gene Expression in Human Coronary Arteries

Abstract

S U M M A R YThe natriuretic peptides (NPs) ANF, BNP, and CNP have potent anti-proliferative and anti-migratory effects on vascular smooth muscle cells (SMCs). These properties make NPs relevant to the study of human coronary atherosclerosis because vascular cell proliferation and migration are central to the pathophysiology of atherosclerosis. However, the existence and cytological distribution of NPs and their receptors in human coronary arteries remain undetermined. This has hampered the development of hypotheses regarding the possible role of NPs in human coronary disease. We determined the pattern of expression of NPs and their receptors (NPRs) in human coronary arteries with atherosclerotic lesions classified by standard histopathological criteria as fatty streak/early atherosclerotic lesions, intermediate plaques, or advanced lesions. The investigation was carried out using a combination of immunocytochemistry (ICC), in situ hybridization (ISH), and semiquantitative polymerase chain reaction (PCR). Both by ICC and ISH, ANF was found in the intimal and medial layers of all lesions. BNP was highly expressed in advanced lesions where it was particularly evident by a strong ISH signal but weak ICC staining. CNP was demonstrable in all types of lesions, giving a strong signal by ISH and ICC. This peptide was particularly demonstrable in the endothelium, as well as in the SMCs of the intima, media, and vasa vasorum of the adventitia and in macrophages. By ISH, NPR-A was not detectable in any of the lesions but both NPR-B and NPR-C were found in the intimal and the inner medial layers. By RT-PCR, mRNA levels of all NPs tended to be increased in macroscopically diseased arteries, but only the values for BNP were significantly so. No significant changes in NPR mRNA levels were detected by PCR. In general, the signal intensity given by the NPs and their receptors by ICC or ISH appeared dependent on the type of lesion, being strongest in intermediate plaques and decreasing with increasing severity of the lesion. This study constitutes the first demonstration of NPs and NPR mRNAs in human coronary arteries and supports the existence of an autocrine/paracrine NP system that is actively modulated during the progression of atherosclerotic coronary disease. This suggests that the coronary NP system is involved in the pathobiology of intimal plaque formation in humans and may be involved in vascular remodeling.

Membrane guanylyl cyclase receptors: an update

“…Furthermore, GCB is expressed at the site of vascular injury. These results and that of others [50] support the concept that CNP and GCB undergo changes in expression in relation to the progression of an atherosclerotic lesion in humans. The prominence of CNP is particularly evident in endothelial cells and in plaque microvessels and adventitial vasa vasorum, and therefore it is reasonable to speculate a role for CNP-GCB signaling in vascular remodeling and in the progression or regression of plaques.…”

N-terminal Pro-B-type Natriuretic Peptide is Associated with Arterial Stiffness as Measured According to the Brachial-ankle Pulse Wave Velocity in Patients with Takayasu Arteritis

“…Recent studies have also demonstrated that myocardial perfusion abnormalities on 201Tl myocardial scintigraphy and late gadolinium enhancement on cardiac magnetic resonance imaging are frequently observed in patients with asymptomatic TA 32,33) . Consequently, subclinical myocardial ischemia may induce the production of NT-proBNP from the intima in human coronary arteries 34) . Hence, the alterations related to increased arterial stiffness may stimulate the synthesis and release of NT-proBNP.…”

Regulation of C-type natriuretic peptide expression

“…These findings have helped establish the major functions of CNP as being either paracrine or autocrine in nature, rather than endocrine. In keeping with its limited range of action, CNP expression is normally confined to those tissues and organs in which it exerts a regulatory role, principally the brain and pituitary [82], cardiovascular system [11,23,38,69,98], endochondral bone [102], and the male [100] and female [95,103] reproductive systems. CNP transcript and/or protein have also been identified in a number of tissues and organs where its functional role has yet to be defined [9,76,77,94].…”

“…A study of CNP expression in human neointimal SMC following angioplasty [56] pointed to a similar, time-dependent up-regulation of CNP in the human SMC that was maintained for at least six months after surgical intervention. Casco et al [11], using immunohistochemistry, identified CNP in both medial and intimal SMC of early through advanced atherosclerotic lesions, but the relationship of CNP to lesion stage was not described. CNP expression has also been studied in human aortic valves with increasing severity of stenosis, a condition that has many of the hallmarks of atherosclerosis, including early inflammation and later fibrosis and calcification [68].…”