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Molecular toxicological alterations in the mouse hearts induced by sub-chronic thiazolidinedione drugs administration
Yazun Bashir Jarrar1, Qais Jarrar2, Sara J Abaalkhail1
1Department of Pharmacy, Al-Zaytoonah University of Jordan, Amman, Jordan.
Abstract:
Thiazolidinediones are well-known anti-diabetic drugs. However, they are not widely used due to their cardiotoxic effects. Therefore, in this study, we aimed to determine the molecular toxicological alterations induced in the mouse hearts after thiazolidinedione administration. Balb/c mice received doses clinically equivalent to those given to humans of the most commonly used thiazolidinediones, pioglitazone, and rosiglitazone for 30 days. After that, RNA samples were isolated from the hearts. The mRNA expression of cytochrome (cyp) p450 genes that synthesize the cardiotoxic 20-hydroxyeicosatetraenoic acid (20-HETE) in addition to 92 cardiotoxicity biomarker genes were analyzed using quantitative polymerase chain reaction array technique. The analysis demonstrated that thiazolidinediones caused a significant upregulation (p < 0.5) of the mRNA expression of cyp1a1, cyp4a12, itpr1, ccl7, ccr1, and b2 m genes. In addition, thiazolidinediones caused a significant (p < 0.05) downregulation of the mRNA expression of adra2a, bsn, col15a1, fosl1, Il6, bpifa1, plau, and reg3b genes. The most affected gene was itpr1 gene, which was upregulated by pioglitazone and rosiglitazone by sevenfold and 3.5-fold, respectively. In addition, pioglitazone caused significant upregulation of (p < 0.05) hamp, ppbp, psma2, sik1, timp1, and ucp1 genes, which were not affected significantly (p > 0.05) by rosiglitazone administration. In conclusion, this study showed that thiazolidinediones induce toxicological molecular alterations in the mouse hearts, such as the induction of cyp450s that synthesize 20-HETE, chemokine activation, inflammatory responses, blood clotting, and oxidative stress. These findings may help us understand the mechanism of cardiotoxicity involved in thiazolidinedione administration.
Insights
Thiazolidinediones, used as anti-diabetic drugs, were found to induce molecular cardiotoxicity in mice. This study reveals gene expression changes in the heart, including upregulation of cytochrome P450s involved in producing cardiotoxic 20-HETE.
Area of Science:
- Toxicology
- Molecular Biology
- Cardiovascular Research
Background:
- Thiazolidinediones are effective anti-diabetic agents but are limited by cardiotoxicity.
- Understanding the molecular mechanisms of this cardiotoxicity is crucial for drug safety.
Purpose of the Study:
- To investigate the molecular toxicological alterations in mouse hearts following administration of thiazolidinediones.
- To identify specific gene expression changes associated with thiazolidinedione-induced cardiotoxicity.
Main Methods:
- Balb/c mice were treated with pioglitazone and rosiglitazone for 30 days.
- Quantitative polymerase chain reaction (qPCR) array was used to analyze mRNA expression of cytochrome P450 genes and 92 cardiotoxicity biomarkers.
- Key genes analyzed included those involved in 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis.
Main Results:
- Thiazolidinediones significantly upregulated genes such as cyp1a1, cyp4a12, and itpr1, and downregulated genes including adra2a, Il6, and plau.
- The itpr1 gene showed the most significant upregulation, with a sevenfold increase by pioglitazone and 3.5-fold by rosiglitazone.
- Pioglitazone uniquely upregulated genes like hamp, ppbp, and ucp1, suggesting differential toxicological profiles.
Conclusions:
- Thiazolidinediones induce molecular alterations in the heart, including the induction of CYP450s that synthesize 20-HETE.
- Observed changes indicate thiazolidinedione-induced cardiotoxicity involves chemokine activation, inflammation, blood clotting, and oxidative stress.
- These findings provide insights into the mechanisms underlying thiazolidinedione cardiotoxicity.
