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Myocyte contractility with caspase inhibition and simulated hyperkalemic cardioplegic arrest
Rupak Mukherjee1, William M Yarbrough, Emily S Reese
1Division of Cardiothoracic Surgery Research, Medical University of South Carolina, Charleston, South Carolina 29425, USA. mukherr@musc.edu
Insights
Caspase inhibition during hyperkalemic cardioplegic arrest (HCA) improves left ventricular myocyte function after rewarming. This suggests caspases contribute to contractile dysfunction, offering a potential therapeutic target.
Area of Science:
- Cardiology
- Cellular Biology
- Biochemistry
Background:
- Hyperkalemic cardioplegic arrest (HCA) disrupts ionic balance in left ventricular (LV) myocytes, impairing contractility upon rewarming.
- Altered ionic homeostasis can activate caspases, proteases involved in apoptosis and contractile protein degradation.
- This study investigates if caspase inhibition mitigates HCA-induced contractile dysfunction independent of myocyte viability.
Purpose of the Study:
- To test if caspase inhibition during HCA preserves myocyte contractility after rewarming.
- To determine if caspase inhibition affects myocyte viability during HCA.
Main Methods:
- Porcine LV myocytes were subjected to normothermic conditions, HCA, or HCA with a caspase inhibitor (z-VAD).
- Myocyte viability was assessed via mitochondrial function.
- Myocyte shortening velocity was measured to quantify contractility.
Main Results:
- HCA significantly reduced myocyte shortening velocity compared to controls.
- Caspase inhibition (HCA+zVAD) significantly improved myocyte shortening velocity versus HCA alone.
- Myocyte viability remained similar across all treatment groups.
Conclusions:
- Caspase inhibition effectively attenuated myocyte contractile dysfunction post-HCA and rewarming.
- Caspase activation during HCA contributes to impaired myocyte contractility.
- Supplementing HCA with caspase inhibitors may preserve myocyte function.
Background:
Exposure of left ventricular (LV) myocytes to simulated hyperkalemic cardioplegic arrest (HCA) has been demonstrated to perturb ionic homeostasis and adversely affect myocyte contractility on rewarming. Altered ionic homeostasis can cause cytosolic activation of the caspases. While caspases participate in apoptosis, these proteases can degrade myocyte contractile proteins, and thereby alter myocyte contractility. Accordingly, this study tested the hypothesis that caspase inhibition during HCA would attenuate the degree of myocyte contractile dysfunction upon rewarming, independent of a loss in myocyte viability.
Methods:
Porcine (n = 8) LV myocytes were isolated and assigned to the following treatment groups: normothermic control: incubation in cell culture media for 2 hours at 37 degrees C; HCA only: incubation for 2 hours in hypothermic HCA solution (4 degrees C, 24 mEq K(+)); or incubation in hypothermic HCA solution supplemented with 10 microM of the caspase inhibitor, z-VAD (z-Val-Ala-Asp-fluoromethyl-ketone, HCA+zVAD). Myocyte viability, assayed as a function of mitochondrial function, was determined to be similar in the normothermic and both HCA groups.
Results:
The HCA caused a significant reduction in myocyte shortening velocity compared with normothermic control values (41 +/- 6 versus 86 +/- 8 microm/s, p < 0.05). The HCA+zVAD group had significantly improved myocyte shortening velocity compared with the HCA only group (63 +/- 7 microm/s, p < 0.05).
Conclusions:
Independent of changes in viability, caspase inhibition attenuated myocyte contractile dysfunction after HCA and rewarming. Thus, caspase activation during HCA contributes, at least in part, to impaired myocyte contractility with rewarming. Supplementation of HCA with caspase inhibitors may provide a means to preserve myocyte contractile function after cardioplegic arrest.
