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Cardiac phosphocreatine deficiency induced by GPA during postnatal development in rat
V Pelouch1, F Kolár, Z A Khuchua
1Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Insights
Chronic beta-guanidinopropionic acid (GPA) administration impairs developing rat heart function by altering energy metabolism and protein profiles. This study highlights the creatine kinase system's importance in cardiac health and growth.
Area of Science:
- Cardiovascular Physiology
- Biochemistry
- Molecular Biology
Background:
- Beta-guanidinopropionic acid (GPA) is a creatine analog that can disrupt cellular energy metabolism.
- The developing heart is particularly vulnerable to metabolic disturbances.
- Understanding the impact of GPA on cardiac function and protein expression is crucial for cardiovascular health research.
Purpose of the Study:
- To investigate the effects of chronic GPA administration on protein profiling, energy metabolism, and right ventricular (RV) function in developing rat hearts.
- To elucidate the role of the creatine kinase (CK) system in mediating these effects.
- To assess the impact on cardiac growth and contractile performance.
Main Methods:
- Chronic oral administration of GPA (1-1.5%) to rats during weaning and adolescence.
- Measurement of cardiac tissue GPA accumulation, creatine, phosphocreatine, and ATP levels.
- Analysis of creatine kinase (CK) isoenzyme distribution (Mi-CK, MB-CK).
- Assessment of cardiac collagenous and non-collagenous protein content.
- Evaluation of RV function using an isolated perfused heart model with pressure-volume analysis.
Main Results:
- GPA accumulated in the myocardium, significantly decreasing total creatine, phosphocreatine, and ATP levels.
- CK activity was unchanged, but Mi-CK proportion decreased and MB-CK increased.
- Cardiac collagenous proteins increased, non-collagenous proteins decreased, and the collagen I/III ratio was reduced.
- RV function was significantly impaired, with reduced systolic pressure, rate of pressure development, and cardiac output.
- Blood plasma glucose, total lipids, and triglycerides remained unaffected.
Conclusions:
- Chronic GPA administration profoundly impacts metabolic parameters, protein profiles, and contractile function in the developing heart.
- The CK system is central to heart function and cardiac myocyte growth regulation.
- GPA-induced metabolic disruption leads to impaired RV function and altered cardiac protein composition.
Abstract:
The effect of chronic administration of beta-guanidinopropionic acid (GPA) on the protein profiling, energy metabolism and right ventricular (RV) function was studied in the rat heart during the weaning and adolescence period. GPA was given in tap water (1-1.5%) using pair drink controls. The feeding of animals with GPA solution for a six week period resulted in elevation of heart to body weight ratio due to body growth retardation. GPA accumulated in the myocardium up to 67.37 +/- 5.3 mumoles.g dry weight and the tissue content of total creatine, phosphocreatine and ATP was significantly decreased to 15%, 9% and 65% of control values respectively. Total activity of creatine kinase (CK) was not changed, but the proportion of mitochondrial (Mi) CK isoenzyme was decreased; the percentage of MB isoenzyme of CK was significantly higher. GPA treatment resulted in an elevation of the content of cardiac collagenous proteins and decrease of non-collagenous proteins in the heart; in parallel, a decrease of the collagen I to collagen III ratio was detected. The function of the RV was assessed using an isolated perfused heart with RV performing pressure-volume work. As compared to pair-drink controls, RV function was significantly impaired the GPA group: at any given right atrial filling pressure, the RV systolic pressure and the rate of pressure development were decreased by almost a factor of two. Elevation of the RV diastolic pressure with increasing pulmonary artery diastolic pressure was also significantly steeper in the GPA group which also showed decrease of cardiac output, especially at high outflow resistance. It may be assumed that chronic administration of GPA deeply influenced metabolic parameters, protein profiles and contractile function of the developing heart. On the other hand, concentrations of glucose, total lipids and triglycerides in blood plasma were not affected. All these data confirm the concept that the CK system is of central importance both for heart function and for the regulation of normal growth of cardiac myocytes.