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Published on: September 9, 2020
Cardiac-specific overexpression of GTP cyclohydrolase 1 restores ischaemic preconditioning during hyperglycaemia
Zhi-Dong Ge1, Irina A Ionova, Nikolina Vladic
1Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. zdge@mcw.edu
Insights
Hyperglycaemia impairs heart protection during reperfusion injury. Overexpressing GTPCH-1 in heart cells restores this protection by increasing tetrahydrobiopterin (BH(4)) and nitric oxide (NO).
Area of Science:
- Cardiovascular Science
- Mitochondrial Biology
- Metabolic Disease
Background:
- Hyperglycaemia (HG) reduces intracellular tetrahydrobiopterin (BH(4)), potentially contributing to myocardial injury during ischaemia and reperfusion.
- Ischaemic preconditioning (IPC) typically protects the heart, but its efficacy is diminished under hyperglycaemic conditions.
Purpose of the Study:
- To investigate if increasing BH(4) via cardiomyocyte-specific GTP cyclohydrolase 1 (GTPCH-1) gene overexpression can rescue myocardial and mitochondrial protection during HG.
- To determine if this protective effect is mediated through a nitric oxide (NO)-dependent pathway.
Main Methods:
- Mice underwent myocardial ischaemia/reperfusion with or without IPC, in the presence or absence of HG induced by d-glucose.
- Cardiomyocyte-specific GTPCH-1 overexpression was employed in genetically modified mice.
- Mitochondrial permeability transition pore opening was assessed using isolated mitochondria and calcium concentrations.
Main Results:
- IPC reduced infarct size in wild-type mice, but this protection was abolished by HG.
- GTPCH-1 overexpression restored IPC-mediated cardioprotection during HG, decreasing infarct size.
- The protective effects of GTPCH-1 overexpression were attenuated by a nitric oxide synthase inhibitor, indicating NO dependency.
- IPC increased mitochondrial Ca(2+) threshold for pore opening, an effect reversed by HG and rescued by GTPCH-1 overexpression.
Conclusions:
- Elevated BH(4) levels, achieved through cardiomyocyte-specific GTPCH-1 overexpression, preserve the cardioprotective effects of IPC that are compromised by hyperglycaemia.
- This preservation of myocardial and mitochondrial function appears to be critically dependent on nitric oxide signaling.
Aims:
Hyperglycaemia (HG) decreases intracellular tetrahydrobiopterin (BH(4)) concentrations, and this action may contribute to injury during myocardial ischaemia and reperfusion. We investigated whether increased BH(4) by cardiomyocyte-specific overexpression of the GTP cyclohydrolase (GTPCH) 1 gene rescues myocardial and mitochondrial protection by ischaemic preconditioning (IPC) during HG through a nitric oxide (NO)-dependent pathway.
Methods And Results:
Mice underwent 30 min of myocardial ischaemia followed by 2 h of reperfusion with or without IPC elicited with four cycles of 5 min ischaemia/5 min of reperfusion in the presence or absence of HG produced by d-glucose. In C57BL/6 wild-type mice, IPC increased myocardial BH(4) and NO concentrations and decreased myocardial infarct size (30 ± 3% of risk area) compared with control (56 ± 5%) experiments. This protective effect was inhibited by HG (48 ± 3%) but not hyperosmolarity. GTPCH-1 overexpression increased myocardial BH(4) and NO concentrations and restored cardioprotection by IPC during HG (32 ± 4%). In contrast, a non-selective NO synthase inhibitor N(G)-nitro-l-arginine methyl ester attenuated the favourable effects of GTPCH-1 overexpression (52 ± 3%) during HG. Mitochondria isolated from myocardium subjected to IPC required significantly higher in vitro Ca(2+) concentrations (184 ± 14 µmol mg(-1) protein) to open the mitochondrial permeability transition pore when compared with mitochondria isolated from control experiments (142 ± 10 µmol mg(-1) protein). This beneficial effect of IPC was reversed by HG and rescued by GTPCH-1 overexpression.
Conclusion:
Increased BH(4) by cardiomyocyte-specific overexpression of GTPCH-1 preserves the ability of IPC to elicit myocardial and mitochondrial protection that is impaired by HG, and this action appears to be dependent on NO.
