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Published on: September 28, 2015
Olmesartan prevents cardiac rupture in mice with myocardial infarction by modulating growth differentiation factor 15
1State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Guangzhou, China.
Background And Purpose:
Cardiac rupture is a catastrophic complication that occurs after acute myocardial infarction (MI) and, at present, there are no effective pharmacological strategies for preventing this condition. Here we investigated the effect of the angiotensin II receptor blocker olmesartan (Olm) on post-infarct cardiac rupture and its underlying mechanisms of action.
Experimental Approach:
C57Bl/6 mice with MI were treated with Olm, aldosterone (Aldo) or vehicle. Cultured neonatal cardiomyocytes and fibroblasts were exposed to normoxia or anoxia and treated with angiotensin II (Ang II), RNH6270 (active ingredient of Olm) or Aldo.
Key Results:
The mortality rate and incidence of cardiac rupture in MI mice during the first week in the Olm-treated group were significantly lower than in the vehicle-treated group. Olm or RNH6270 reduced myeloperoxidase staining in the infarcted myocardium, decreased apoptosis in cultured cardiomyocytes and fibroblasts, as assessed by Hoechst staining and TUNEL assay, attenuated the accumulation of p53 and phosphorylated p53 and cleaved caspase 3 induced by MI or Ang II, as assessed by Western blotting, and up-regulated growth differentiation factor-15 (GDF-15). In cultured cardiomyocytes and fibroblasts, treatment with Ang II, Aldo or anoxia significantly down-regulated the expression of GDF-15.
Conclusions And Implications:
Olm prevents cardiac rupture through inhibition of apoptosis and inflammation, which is attributable to the down-regulation of p53 activity and up-regulation of GDF-15. Our findings suggest that early administration of an AT1 receptor anatagonist to patients with acute MI is a potential preventive approach for cardiac rupture.
Insights
Olmesartan significantly reduces cardiac rupture and mortality after myocardial infarction (MI) by inhibiting apoptosis and inflammation. This angiotensin II receptor blocker up-regulates GDF-15 and down-regulates p53 activity, offering a potential preventive strategy for post-MI complications.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Molecular Biology
Background:
- Cardiac rupture is a severe complication following acute myocardial infarction (MI).
- Currently, no effective pharmacological treatments exist to prevent post-MI cardiac rupture.
- Understanding the mechanisms underlying cardiac rupture is crucial for developing preventive strategies.
Purpose of the Study:
- To investigate the efficacy of olmesartan (Olm), an angiotensin II receptor blocker, in preventing post-infarct cardiac rupture.
- To elucidate the underlying mechanisms by which olmesartan exerts its protective effects.
Main Methods:
- Myocardial infarction (MI) was induced in C57Bl/6 mice, followed by treatment with olmesartan (Olm), aldosterone (Aldo), or vehicle.
- In vitro studies involved cultured neonatal cardiomyocytes and fibroblasts exposed to normoxia/anoxia and treated with angiotensin II (Ang II), RNH6270 (active ingredient of Olm), or Aldo.
- Apoptosis, inflammation markers (myeloperoxidase), p53 activity, cleaved caspase 3, and GDF-15 expression were assessed using techniques like Hoechst staining, TUNEL assay, and Western blotting.
Main Results:
- Olmesartan treatment significantly reduced mortality and the incidence of cardiac rupture in MI mice compared to vehicle control.
- Olmesartan inhibited myeloperoxidase staining in the infarcted myocardium, indicating reduced inflammation.
- Apoptosis in cardiomyocytes and fibroblasts was decreased by olmesartan, evidenced by reduced p53 accumulation and cleaved caspase 3, alongside an up-regulation of GDF-15.
Conclusions:
- Olmesartan effectively prevents cardiac rupture post-MI by suppressing apoptosis and inflammation.
- The protective mechanism involves down-regulation of p53 activity and up-regulation of growth differentiation factor-15 (GDF-15).
- Early administration of AT1 receptor antagonists like olmesartan presents a promising therapeutic approach for preventing cardiac rupture in acute MI patients.
