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[Long-term effects of heme oxygenase 1 overexpression on post-infarction heart function in diabetic rats]
Jian Li1, Tian-Meng Chen, Jianla Cao
1The First Department of Geriatric Cardiology, Chinese PLA General Hospital, Beijing, China.
Insights
Increased heme oxygenase-1 (HO-1) expression improves cardiac function in diabetic rats with myocardial infarction by reducing inflammation and enhancing antioxidant capacity. This study highlights HO-1 as a potential therapeutic target for diabetic heart disease.
Area of Science:
- Cardiology
- Diabetology
- Biochemistry
Background:
- Diabetic cardiomyopathy and myocardial infarction (MI) significantly increase cardiovascular risk.
- Heme oxygenase-1 (HO-1) plays a crucial role in cellular protection against oxidative stress and inflammation.
- The specific impact of HO-1 modulation on cardiac function in diabetic MI remains to be fully elucidated.
Purpose of the Study:
- To investigate the effect of upregulated heme oxygenase-1 (HO-1) on cardiac function and ventricular remodeling in diabetic rats following myocardial infarction (MI).
- To explore the underlying mechanisms, including inflammatory and antioxidant pathways, involved in HO-1's cardioprotective effects.
Main Methods:
- Adult male Wistar rats were induced with diabetes and myocardial infarction, then treated with either an HO-1 inducer (cobalt protoporphyrin, CoPP) or an HO inhibitor (tin porphyrin, SnMP).
- Cardiac function and left ventricular remodeling were assessed using echocardiography and invasive hemodynamic measurements.
- Serum levels of inflammatory markers (hs-CRP, TNF), nitric oxide (NO), prostacyclin (PGI2), and other biochemical parameters were measured via ELISA.
Main Results:
- HO-1 induction with CoPP significantly improved cardiac function, evidenced by enhanced ±dp/dtmax, ejection fraction, and fractional shortening, while reducing left ventricular end-diastolic diameter.
- CoPP treatment led to increased serum bilirubin, NO, and PGI2 levels, alongside elevated myocardial expression of peNOS, pAkt, and pAMPK.
- Conversely, CoPP treatment significantly reduced serum hs-CRP and TNF levels, indicating an anti-inflammatory effect. Cardiac function was impaired in rats treated with the HO inhibitor.
Conclusions:
- Upregulated HO-1 expression ameliorates cardiac dysfunction and ventricular remodeling in diabetic rats post-MI.
- The protective effects are mediated through improved endothelial function, reduced inflammatory responses, and enhanced antioxidant capacity via the peNOS-pAMPK pathway.
- HO-1 modulation represents a promising therapeutic strategy for managing cardiac complications in diabetic patients with myocardial infarction.
Objective:
To clarify the impact of increased heme oxygenase-1 (HO-1) expression on cardiac function of diabetic rats with myocardial infarction and its mechanism.
Methods:
Sixty adult male Wistar rats were randomly divided into five groups (n = 12): sham operation group (sham), diabetes + sham operation group (DM + sham), diabetes + MI group (DM + MI) , diabetes + myocardial infarction + cobalt original porphyrin (CoPP) group (DM + MI + CoPP), diabetes + myocardial infarction + CoPP+ tin porphyrin (SnMP) group (DM + MI + CoPP + SnMP). CoPP 4.5 mg/kg or SnMP 15 mg/kg were administered at the day next to MI operation, for six weeks, once a week. At the 28th week post operation, the echocardiography, left heart via the carotid artery indoor intubation were used to observe the long-term influence of HO-1 inducer (cobalt protoporphyrin, CoPP) and activity of HO inhibitor (tin porphyrin, SnMP) on the indices of left ventricular remodeling and cardiac function after the intervention. Blood glucose (GLU), total cholesterol (TC), C-reactive protein (CRP), serum creatinine (Cr), aminotransferase (ALT) and other indicators were measured. ELISA was used to test interleukin-6 (IL-6), tumor necrosis factor (TNF), nitric oxide (NO), prostacyclin (PGI2), adiponectin, and ultra sensitive CRP (HsCRP) level.
Results:
HO-1 inducer, CoPP, could ameliorate ± dp/dtmax, left ventricular ejection fraction and left ventricular shortening fraction in diabetic myocardial infarction rats. It could also decrease left ventricular end-diastolic diameter. The serum bilirubin, NO and PGI2 levels, myocardial phosphorylated endothelial nitric oxide synthasee(peNOS), phosphorylated activated protein kinase (pAkt), phosphorylated adenosine monophosphate-activated protein kinase (pAMPK) expression were also significantly elevated, and the serum hs-CRP and TNF levels were significantly inhibited. Compared to inducer group, cardiac function were worse in the inhibitor group.
Conclusion:
Upregulated HO-1 level can improve the endothelial function, inhibite of the inflammatory response and enhance the antioxidant substances in serum bilirubin via peNOS-pAMPK pathway, which effectively inhibit ventricular remodeling and improve the long-term cardiac function after infarction in diabetic rats.
