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[A comparative study of cardiac function in transgenic hypertensive rats, in spontaneously hypertensive rats and in
J Bohlender1, U Hildenbrand, W P Schlegel
1Max Delbrück Centrum für Molekulare Medizin (MDC), Berlin-Buch, Allemagne.
Insights
Left ventricular hypertrophy (LVH) involves molecular changes leading to heart failure. In transgenic rats, activated renin-angiotensin system caused early adrenergic dysfunction, indicating progressive cardiac deterioration and need for intervention.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Renal Physiology
Background:
- Left ventricular hypertrophy (LVH) is a precursor to cardiac insufficiency, involving complex molecular and functional changes.
- The renin-angiotensin system (RAS) and adrenergic signaling pathways are implicated in LVH progression and may interact to cause contractile dysfunction.
Purpose of the Study:
- To investigate cardiac function and adrenergic signaling in hypertensive rats with genetically activated RAS (TGR) compared to spontaneously hypertensive rats (SHR) and normotensive controls (CTR).
- To elucidate the impact of RAS activation on cardiac response to beta-adrenergic stimulation and identify underlying molecular mechanisms.
Main Methods:
- Utilized an isolated perfused heart model in 6-week-old TGR, SHR, and CTR rats.
- Assessed cardiac function (Pmax, dP/dt) and response to isoproterenol.
- Analyzed cardiac protein and gene expression using Western blot and RNase protection assay.
Main Results:
- TGR exhibited significantly higher blood pressure and cardiac/body weight ratio than CTR. SHR had elevated blood pressure without significant heart weight changes.
- Basal contractility was higher in TGR and SHR, but isoproterenol failed to stimulate these parameters in TGR, indicating adrenergic dysfunction.
- Isoproterenol induced less vasodilation in TGR. Gi alpha protein was increased, and converting enzyme and atrial natriuretic factor mRNA were upregulated in TGR hearts.
Conclusions:
- LVH in TGR is characterized by early adrenergic signaling abnormalities and beta-1 receptor dysfunction, suggesting progressive deterioration.
- These findings support early intervention strategies for angiotensin-II-dependent cardiac hypertrophy and have implications for patients with RAS genetic alterations.
Abstract:
Left ventricular hypertrophy (LVH) entails numerous functional and molecular changes that ultimately lead to cardiac insufficiency. The renin-angiotensin system and adrenergic receptor signalling pathway have both been implicated in LVH progression and interactions between these factors may precipitate contractile dysfunction. We therefore investigated cardiac function in hypertensive rats transgenic for the human renin and angiotensinogen genes (TGR) having a genetic activation of the renin-angiotensin system, stroke-prone spontaneously hypertensive rats (SHR) and normotensive controls (CTR) aged 6 weeks. The isolated perfused heart model was used and the effect of isoproterenol (0.1-1000 nmol/L on cardiac function was studied. Cardiac protein and gene expression was studied by Western blot and RNase protection assay. TGR had 75 mmHg higher blood pressure and a 24% higher cardiac/body weight ratio than CTR; blood pressure in SHR was 17 mmHg higher without heart weight difference (p < 0.05). Basal Pmax, +dP/dt and -dP/dt were higher in TGR and SHR compared with CTR hearts. Isoproterenol stimulated these parameters by a maximum factor 6-8 in CTR and SHR but had almost no effect in TGR (p < 0.05). Basal CF per g heart weight was similar in all experimental groups. Isoproterenol produced a significantly smaller vasodilation in TGR compared with CTR or SHR. beta 1 and beta 2 receptor and Gs alpha proteins were similar in TGR, SHR and CTR. Gi alpha was increased in TGR hearts (p < 0.05). Converting enzyme and atrial natriuretic factor mRNA expression was increased (p < 0.01) while beta 1 receptor, adenylyl-cyclase V, SERCA2a and phospholamban mRNA expression was unchanged in TGR compared with CTR. Thus, LVH in TGR is characterised by early adrenergic dysfunction and beta 1 receptor signalling abnormalities indicating progressive functional deterioration. The data may serve as support for an early preventive intervention in angiotensin-II dependent cardiac hypertrophy and may have also implications for patients with genetic alterations of the renin-angiotensin system.