Induction of Heme Oxygenase with Hemin Improves Impaired Insulin Signaling and Compromised Cardiac Structure and Function in Obese Zucker Rats
Bibliographic record
Abstract
Background Diabetic cardiomyopathy is characterized by cardiac dysfunction and impaired insulin signaling. The mechanisms that drive obesity and insulin‐resistant mediated cardiomyopathy are not completely elucidated. Accordingly, the aim of this study was to examine the effects of upregulating the heme‐oxygenase (HO) on obesity related cardiac dysfunction and impaired insulin signaling in obese Zucker rats, a model characterized by insulin resistance and cardiomyopathy. Methods Immunohistochemistry, spectrophotometry, enzyme‐linked immunosorbent assay (ELISA) and Western blotting were used. In addition non‐invasive echocardiography and invasive left ventricular (LV) cannulation was employed to evaluate the hemodynamic, echocardiographic and electrophysiological parameters of the myocardium. HO was enhanced with hemin or blocked with stannous mesoporphyrin. Results Our data demonstrated that administering hemin to obese Zucker rats; (i) enhanced important proteins of insulin signaling (IRS‐1, PI3K and GLUT4), (ii) reduced glucose intolerance, (iii) suppressed HOMA‐index, but (iv) increased adiponectin and atrial‐natriuretic‐peptide (ANP). Interestingly, the improvement of insulin sensitivity and glucose metabolism was accompanied by attenuation of cardiomyocytes longitudinal muscle‐fiber thickness, the reduction of diastolic/systolic free‐wall thickness and the suppression of LV hypertrophy. Furthermore, hemin attenuated inflammation/oxidative stress, suppressed fibrosis, extracellular matrix/pro‐fibrotic proteins (collagen‐IV, fibronectin, TGF‐β1) as well as proteins of heart failure such as osteopontin and osteoprotegerin. These were associated with improved cardiac function as evidenced by improved hemodynamics such as mean‐arterial pressure, arterial‐systolic pressure, +dP/dt, arterial‐diastolic pressure and improved electrocardiographic parameters associated with cardiac conduction system including PR‐interval, QRS‐duration, ST‐segment and QT interval. However, the HO blocker, stannous‐mesoporphyrin reversed the cardio‐protective effects of hemin. Conclusion Our findings demonstrates that hemin improved compromised cardiac structure and function in obese Zucker rats. Interestingly, attenuation of inflammation, oxidative stress, extracellular‐matrix/profibrotic proteins, cardiac hypertrophy and fibrosis alongside the potentiation of adiponectin, ANP and proteins of insulin signaling are among the multifaceted mechanisms through which an upregulated HO‐system improves insulin sensitivity, glucose metabolism and diabetic cardiomyopathy. Thus, HO‐inducers may be explored as a novel therapy for diabetic cardiomyopathy. Support or Funding Information Heart & Stroke Foundation of Saskatchewan, Canada
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".