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Selective activation of cardiac angiotensinogen gene expression in post-infarction ventricular remodeling in the rat
K Lindpaintner1, W Lu, N Neidermajer
1Department of Cardiology, Children's Hospital, Boston, MA 02115.
Abstract:
Recent studies in both experimental animals and man have demonstrated the unique efficacy of converting enzyme inhibitors to prevent or attenuate ventricular remodeling after myocardial infarction. Concomitantly, evidence for a trophic role of the renin-angiotensin system (RAS), as well as for the existence of an intracardiac tissue-resident RAS, has been presented, raising the question whether altered regulation of this cardiac RAS may be associated with the process of ventricular remodeling. We conducted the present study to examine whether cardiac angiotensinogen gene expression is altered after myocardial infarction. Experiments were performed in rats 5 and 25 days after ligation of the left coronary artery or sham operation. Coronary artery ligation resulted in relative infarct sizes averaging 29% and 36% of total left ventricular mass at 5 and 25 days and in marked elevations of left ventricular end-diastolic pressure (LVEDP). Angiotensinogen mRNA levels, measured by solution hybridization assay and confirmed in a second, independent experimental group by RNAse protection assay, were significantly elevated in the non-infarcted portion of the left ventricle at 5 days after infarction when compared to the sham group (22.1 + 3.3 vs. 13.4 +/- 2.0 fg/microgram total RNA; ratio of densitometric absorbance for angiotensinogen/beta-actin: 0.356 +/- 0.041 vs. 0.156 +/- 0.02), and showed a significant correlation with infarct size (r = 0.93). At 25 days, angiotensinogen gene expression had returned to control values. Similarly, no significant differences in angiotensinogen mRNA levels between animals with and without infarction were found in other cardiac tissues (atria, right ventricle). Plasma renin activity was significantly increased over baseline in the infarct group at 5, but not at 25 days. Our results demonstrate that acute hemodynamic embarrassment early after LV infarction is associated with augmented angiotensinogen gene expression. The potential significance of this finding is discussed.
Insights
Myocardial infarction increases cardiac angiotensinogen gene expression early after injury, correlating with infarct size. This expression returns to normal levels by 25 days post-infarction.
Area of Science:
- Cardiovascular Research
- Molecular Cardiology
- Renal Physiology
Background:
- Converting enzyme inhibitors show efficacy in preventing ventricular remodeling post-myocardial infarction.
- The renin-angiotensin system (RAS) plays a trophic role, with evidence for an intracardiac RAS.
- Altered cardiac RAS regulation may contribute to ventricular remodeling.
Purpose of the Study:
- To investigate alterations in cardiac angiotensinogen gene expression following myocardial infarction.
- To determine if intracardiac RAS is modulated in response to left ventricular infarction.
Main Methods:
- Myocardial infarction induced in rats via left coronary artery ligation.
- Gene expression analysis of angiotensinogen mRNA using solution hybridization and RNAse protection assays.
- Measurement of left ventricular end-diastolic pressure and plasma renin activity.
Main Results:
- Angiotensinogen mRNA levels significantly elevated in the non-infarcted left ventricle 5 days post-infarction (p<0.05).
- Elevated angiotensinogen expression correlated significantly with infarct size (r=0.93).
- Angiotensinogen gene expression returned to control levels by 25 days; no changes in atria or right ventricle.
Conclusions:
- Acute hemodynamic changes post-myocardial infarction are associated with increased cardiac angiotensinogen gene expression.
- This early upregulation of angiotensinogen may be a key factor in the cardiac response to infarction.
- Further research is needed to elucidate the precise role of this augmented expression in ventricular remodeling.