adrenomedullin and Carotid-Stenosis

Plasma biomarkers may be useful to detect healthy individuals at increased risk for atherosclerotic manifestations, such as carotid artery stenosis. The aim of this longitudinal cohort study was to evaluate new biomarkers in relation to C-reactive protein and conventional risk factors for carotid artery stenosis during long term follow-up METHODS: The following markers were measured in 5550 middle-aged subjects: C-reactive protein, lipoprotein-associated phospholipase A2, proneurotensin, midregional pro-adrenomedullin, midregional pro-atrial natriuretic peptide, N-terminal pro B-type natriuretic peptide, copeptin, and cystatin C. Subjects with prevalent carotid artery stenosis were excluded. Subjects were followed in national patient registers for 23.4 (interquartile range 19.5-24.3) years regarding incident carotid artery stenosis, both operated and non-operated.. When including conventional risk markers in Cox regression, N-terminal pro B-type natriuretic peptide (Hazard ratio 1.36; 95% confidence interval 1.12-1.65; p = 0.002) was independently associated with incident carotid artery stenosis, whereas there were trends for C-reactive protein (HR 1.20; 95% confidence interval 0.98-1.48; p = 0.071), and midregional pro-adrenomedullin (Hazard ratio 1.21; 95% confidence interval 0.99-1.47; p = 0.061). Midregional pro-adrenomedullin (Hazard ratio 1.30; 95% confidence interval 1.03-1.65; p = 0.029) was independently associated with incident surgery for carotid artery stenosis, whereas there was a trend for N-terminal pro B-type natriuretic peptide (Hazard ratio 1.31; 95% confidence interval 1.00-1.72; p = 0.052).. N-terminal pro B-type natriuretic peptide and midregional pro-adrenomedullin can be used as predictors for clinically detected carotid artery stenosis during long-term follow-up of healthy subjects.

Topics: Adrenomedullin; Biomarkers; Carotid Stenosis; Female; Follow-Up Studies; Humans; Incidence; Longitudinal Studies; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Prospective Studies; Protein Precursors; Registries; Risk Assessment; Risk Factors; Sweden; Time Factors

The accessory protein RAMP2 is a component of the CLR/RAMP2 dimeric adrenomedullin (AM) receptor and is the primary determinant of the vascular functionality of AM. RAMP2 is highly expressed in the brain; however, its function there remains unclear. We therefore used heterozygous RAMP2 knockout (RAMP2+/-) mice, in which RAMP2 expression was reduced by half, to examine the actions of the endogenous AM-RAMP2 system in cerebral ischemia. To induce acute or chronic ischemia, mice were subjected to middle cerebral artery occlusion (MCAO) or bilateral common carotid artery stenosis (BCAS), respectively. In RAMP2+/- mice subjected to MCAO, recovery of cerebral blood flow (CBF) was slower than in WT mice. AM gene expression was upregulated after infarction in both genotypes, but the increase was greater in RAMP2+/- mice. Pathological analysis revealed severe nerve cell death and demyelination, and a higher level of oxidative stress in RAMP2+/- mice. In RAMP2+/- mice subjected to BCAS, recovery of cerebral perfusion was slower and less complete than in WT mice. In an 8-arm radial maze test, RAMP2+/- mice required more time to solve the maze and showed poorer reference memory. They also showed greater reductions in nerve cells and less compensatory capillary growth than WT mice. These results indicate the AM-RAMP2 system works to protect nerve cells from both acute and chronic cerebral ischemia by maintaining CBF, suppressing oxidative stress, and in the case of chronic ischemia, enhancing capillary growth.

Topics: Adrenomedullin; Animals; Blood Vessels; Brain; Brain Ischemia; Carotid Stenosis; Cell Death; Humans; Mice; Mice, Knockout; Neurons; Oxidative Stress; Receptor Activity-Modifying Protein 2; Receptors, Adrenomedullin

Adrenomedullin (AM) is a potent vasodilator expressed in tissues relevant to cardiovascular function. AM peptide has been shown to inhibit the proliferation and migration of vascular smooth muscle cells in vitro. However, the effect of AM on blood vessels after vascular injury in vivo has not been elucidated. In order to explore the potential roles of AM in vascular biology, we evaluated the effect of AM by local gene delivery on neointima formation in balloon-injured rat artery. Adenovirus carrying the human AM cDNA under the control of cytomegalovirus promoter/enhancer (Ad.CMV-hAM) was generated by homologous recombination. After delivery of Ad.CMV-hAM into rat left carotid artery, we identified the expression of human AM mRNA in the left carotid artery, but not in the right carotid artery, heart or kidney by reverse transcription-polymerase chain reaction (RT-PCR) followed by Southern blot analysis. Following local AM gene delivery, we observed a 51% reduction in intima/media ratio at the injured site as compared with that of control rats injected with the luciferase gene (n=7, P<0.01). AM gene transfer resulted in regeneration of endothelium as compared to the control. AM gene delivery significantly increased cGMP levels in balloon-injured arteries. These results indicate that AM contributes to reduction of neointima formation by promotion of re-endothelialization and inhibition of vascular smooth muscle cell proliferation via cGMP-dependent signaling pathway.

Topics: Adenoviridae; Adrenomedullin; Angioplasty, Balloon; Animals; Arterial Occlusive Diseases; Carotid Arteries; Carotid Stenosis; Cyclic AMP; Cyclic GMP; Gene Expression; Genetic Vectors; Humans; Models, Biological; Peptides; Rats; RNA, Messenger; Tunica Intima