Regulation of cardiac angiotensin-converting enzyme and angiotensin AT1 receptor gene expression in Npr1 gene-disrupted mice.
1. Understanding of the regulatory mechanisms of gene expression in the control of blood pressure and fluid volume is a key issue in cardiovascular medicine. Guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) signalling antagonizes the physiological and pathophysiological effects mediated by the renin-angiotensin-aldosterone system (RAAS) in the regulation of cardiovascular homeostasis. 2. The targeted-disruption of the Npr1 gene (coding for GC-A/PRA) leads to activation of the cardiac RAAS involved in the hypertrophic remodelling process, which influences cardiac size, expression of pro-inflammatory cytokine genes and the behaviour of various hypertrophy marker genes. The Npr1 gene-knockout (Npr1(-/-)) mice exhibit 35-40 mmHg higher systolic blood pressure and a significantly greater heart weight to bodyweight ratio than wild-type (Npr1(+/+)) mice. 3. The expression of both angiotensin-converting enzyme (ACE) and angiotensin II AT(1a) receptors are significantly increased in hearts from Npr1(-/-) mice compared with hearts from Npr1(+/+) mice. In parallel, the expression of interleukin-6 and tumour necrosis factor-alpha is also markedly increased in hearts from Npr1(-/-) mice. 4. These findings indicate that disruption of NPRA/cGMP signalling leads to augmented expression of the cardiac RAAS in conjunction with pro-inflammatory cytokines in Npr1-null mutant mice, which promotes the development of cardiac hypertrophy and remodelling.
Department of Physiology, Tulane University Health Sciences Center, School of Medicine, New Orleans, Louisiana 70112, USA. kpandey@tulane.edu
Kailash N
KN
Pandey
Elangovan
E
Vellaichamy
D000818:Animals; D006332:Cardiomegaly / Q000503:physiopathology; D005355:Fibrosis; D015870:Gene Expression / Q000502:physiology; D006162:Guanylate Cyclase / Q000502:physiology; D006321:Heart / Q000502:physiology; D006977:Hypertension, Renal / Q000503:physiopathology; D015850:Interleukin-6 / Q000502:physiology; D007668:Kidney / Q000502:physiology; D051379:Mice; D007703:Peptidyl-Dipeptidase A / Q000502:physiology*; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology*; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics* / Q000502:physiology; D012084:Renin-Angiotensin System / Q000502:physiology
D015850:Interleukin-6; D044140:Receptor, Angiotensin, Type 1; D007703:Peptidyl-Dipeptidase A; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A