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20th World Congress on Heart Disease



Kailesh N. Pandey, Ph.D., Tulane University Health Sciences Center, New Orleans, LA, USA


Atrial natriuretic peptide (ANP) was discovered over 30 years ago in the atrium of heart and has been extensively investigated with regard to physiology, pathophysiology, and cardiovascular disease therapeutics. ANP and brain natriuretic peptide (BNP) bind to guanylyl cyclase-A/natriuretic peptide receptor-A (GC-A/NPRA), which produces the intracellular second messenger cGMP and exhibit diuretic, natriuretic, and vasorelaxant effects with novel properties, including antihypertrophic, antifibrotic, antiproliferative, and antiinflammatory actions with a pivotal role in cardiovascular remodeling. GC-A/NPRA signaling antagonizes the cellular and physiological effects mediated by the renin-angiotensin-aldosterone system (RAAS). Genetic disruption of Npr1 (coding for GC-A/NPRA) increases 35-40 mmHg higher systolic blood pressure and a 63% greater heart weight/body weight (HW/BW) ratio leading to congestive heart failure in null mutant (Npr1-/-) mice compared with wild-type (WT; Npr1+/+) mice. The expression levels of angiotensin-converting enzyme (ACE) and angiotensin II type 1a receptor (AT1a) mRNA were increased by 4- to -5fold in Npr1-/- mice hearts compared with the WT mice hearts. The cardiac angiotensin II and aldosterone levels were also significantly increased in Npr1-/- mice than WT controls. Concomitantly, the expression of interleukin-2 (Il-2), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor-1 (TGF-1) were also increased by 4- to 5-fold, in null mutant mice hearts as compared with WT mice. The expression of nuclear factor-kappa B (NF-kB) and its binding activity in the nuclear extracts of Npr1-/- mice hearts was increased by 3- to 4-fold compared with WT mice. Treatment with captopril or hydralazine equally reduced the blood pressure, but only captopril significantly decreased the HW/BW ratio and proinflammatory cytokine gene expression in Npr1-/- mice hearts. The results suggest that the disruption of ANP/NPRA/cGMP signaling leads to augmented expression and activation of RAAS-mediated signaling pathways that enhance the expression of proinflammatory cytokines and promote cardiac hypertrophy, dysfunction, and heart failure.



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