Abstract 059: Cardiovascular injury associated with Transient Receptor Potential Melastatin 7 (TRPM7) downregulation and Mg <sup>2+</sup> deficiency involve calpain.
Bibliographic record
Abstract
Introduction: Transient Receptor Potential Melastatin 7 (TRPM7) is a cation channel bound to a kinase domain important for cellular Mg 2+ homeostasis. We previously demonstrated that TRPM7 is cardiovascular protective and that TRPM7 downregulation and associated Mg 2+ deficiency are associated with cardiovascular inflammation and fibrosis. Here, we investigated underlying molecular mechanisms by studying hearts, cardiac fibroblasts (CF) and small arteries from wild-type (WT) and TRPM7-deficient mice (M7+/Δ) focusing on calpain, a downstream target of TRPM7 kinase. Methods: Hearts and primary culture CF from WT and M7+/Δ mice were used to probe intracellular signaling pathways and pro-fibrotic proteins. Mg 2+ influx was assessed by fluorescence. Protein expression was assessed by immunoblotting. To evaluate direct vascular effects of TRPM7 activation, we studied effects of naltriben, a TRPM7 activator in vessels exposed to low Mg 2+ conditions (0.2mM), to mimic M7+/Δ. Vascular function was assessed by wire myography. Results: Hearts from M7+/Δ had increased collagen deposition (3.3% vs WT: 1.6%). CF M7+/Δ showed reduced influx of Mg 2+ (106% vs WT 115%) and increased expression of TGFβ1 (2.14±0.38 vs WT 0.25±0.19) and phospho-SMAD3 (1.21±0.06 vs WT 0.72±0.05). This was associated with increased expression of fibronectin in CF M7+/Δ vs WT (0.99±0.18 vs 0.42±0.12), α-SMA (1.51±0.13 vs 0.55±0.99) and periostin (1.33±0.24 vs 0.42±0.09). Expression of TGFβ1 and phospho-SMAD3 was normalized by Mg 2+ treatment. CF M7+/Δ exhibited increased calpain-2 (1.55±0.22 vs WT 0.55±0.07) and reduced annexin-A1 (0.56±0.04 vs WT 1.40±0.08), known target proteins of TRPM7-kinase. Treatment with calpastatin (10 -5 M), a calpain inhibitor, normalized expression of TGFβ1, fibronectin and α-SMA. Low Mg 2+ treated vessels exhibited increased contraction induced by U46619 (Emax% 348 vs veh 203) and reduced sensitivity to relaxation by Ach (LogEC50 6.1 vs veh 6.8) and SNP (LogEC50 5.9 vs veh 6.5). Naltriben ameliorated contraction and SNP-relaxation (p<0.05). Summary and Conclusion: Upregulation of cardiac pro-fibrotic and pro-inflammatory processes in M7+/Δ was ameliorated by Mg 2+ and calpastatin. Vascular dysfunction in Mg 2+ -deprived vessels was normalized by TRPM7 activation. Together our findings indicate that cardiovascular injury in TRPM7-deficient states involves calpain and that Mg 2+ /TRPM7 activation is cardiovascular protective.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".