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NO and PGI(2) in coronary endothelial dysfunction in transgenic mice with dilated cardiomyopathy
Lukasz Drelicharz1, Valery Kozlovski, Tomasz Skorka
1Dept. of Experimental Pharmacology, Jagiellonian University Medical College, Grzegorzecka 16, Krakow, 31-531, Poland.
Insights
Dilated cardiomyopathy in Tgalphaq*44 mice shows impaired NO-dependent coronary function and increased PGI(2) in late stages. This endothelial dysfunction may stem from excessive O(2)(-) production by cardiac NADPH oxidase.
Area of Science:
- Cardiovascular Research
- Molecular Cardiology
- Endothelial Biology
Background:
- Dilated cardiomyopathy (DCM) is a progressive heart muscle disease characterized by ventricular dilation and impaired systolic function.
- Endothelial dysfunction plays a crucial role in the pathogenesis of various cardiovascular diseases, including heart failure.
- Transgenic mouse models are essential tools for investigating the molecular mechanisms underlying DCM.
Purpose of the Study:
- To investigate coronary endothelial function in a transgenic mouse model of dilated cardiomyopathy (Tgalphaq*44 mice).
- To assess the impact of DCM on nitric oxide (NO)-dependent and prostacyclin (PGI(2))-dependent vasodilation.
- To explore the underlying mechanisms of endothelial dysfunction in this DCM model.
Main Methods:
- Assessment of coronary vasodilatation (NO-dependent and PGI(2)-dependent) in isolated hearts of Tgalphaq*44 and FVB mice.
- In vivo cardiac function analysis using Magnetic Resonance Imaging (MRI).
- Measurement of cardiac superoxide (O(2)(-)) production and assessment of NADPH oxidase activity.
Main Results:
- In young Tgalphaq*44 mice (2-4 months), cardiac function and endothelial function were preserved.
- In older Tgalphaq*44 mice (14-16 months), cardiac function was impaired, with altered NO-dependent, but not PGI(2)-dependent, coronary function.
- Increased cardiac O(2)(-) production and elevated basal PGI(2) levels were observed in older Tgalphaq*44 mice, linked to NADPH oxidase activity.
Conclusions:
- Endothelial dysfunction in this DCM model emerges in later stages of heart failure.
- The dysfunction is characterized by reduced NO bioavailability and a compensatory increase in PGI(2).
- Excessive superoxide production by cardiac NADPH oxidase is implicated as a key contributor to both NO deficiency and PGI(2) overproduction.
Objective:
The aim of the present work was to analyze coronary endothelial function in the transgenic mouse model of dilated cardiomyopathy (Tgalphaq*44 mice).
Methods:
Coronary vasodilatation, both NO-dependent (induced by bradykinin) and PGI(2)-dependent (induced by acetylcholine), was assessed in the isolated hearts of Tgalphaq*44 and FVB mice. Cardiac function was analyzed in vivo (MRI).
Results:
In Tgalphaq*44 mice at the age of 2-4 months cardiac function was preserved and there were no alterations in endothelial function. By contrast, in Tgalphaq*44 mice at the age of 14-16 months cardiac function was significantly impaired and NO, but not PGI(2)-dependent coronary function was altered. Interestingly, the basal level of PGI(2) in coronary circulation increased fourfold as compared to FVB mice. Cardiac O(2) (-) production increased 1.5-fold and 3-fold in Tgalphaq*44 vs. FVB mice at the age of 2-6 and 14-16 months, respectively, and was inhibited by apocynin. Interestingly, inhibition of NADPH oxidase or NOS-3 normalized augmented PGI(2) production in Tgalphaq*44 mice. There was also an increased expression of gp91phox in Tgalphaq*44 vs. FVB hearts, without evident alterations in the expression of COX-1, COX-2, NOS-3 and PGI(2)-synthase.
Conclusions:
In the mouse model of dilated cardiomyopathy, endothelial dysfunction in coronary circulation is present in the late but not the early stage of heart failure pathology and is characterized by a decrease in NO bioavailability and a compensatory increase in PGI(2). Both the decrease in NO activity and the increase in PGI(2) activity may result from excessive O(2) (-) production by cardiac NADPH oxidase in Tgalphaq*44 hearts.
