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Differential expression of Gs in a murine model of homocysteinemic heart failure
Thomas P Vacek1, Utpal Sen, Neetu Tyagi
1Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA.
Insights
High homocysteine levels downregulate G(s) proteins in mouse hearts, a key factor in heart failure. Homocysteine did not directly alter G protein expression in cell cultures, suggesting indirect in vivo mechanisms.
Area of Science:
- Cardiovascular Physiology
- Molecular Biology
- Biochemistry
Background:
- High plasma homocysteine is a risk factor for heart failure and sudden cardiac death.
- G proteins, including G(s) (stimulatory) and G(i) (inhibitory), regulate calcium and have pathological consequences when overexpressed.
Purpose of the Study:
- To investigate the differential expression of G(s) and G(i) proteins in the hearts of hyperhomocysteinemic (Hhcy) mice.
- To determine if homocysteine (Hcy) acts as an agonist in cell culture to alter G protein isoform expression.
Main Methods:
- Utilized heterozygous cystathionine-beta-synthase (CBS) knockout mice to induce hyperhomocysteinemia.
- Excised cardiac tissue, prepared homogenates, and performed Western blots to analyze G protein expression.
- Treated cultured HL-1 cells with varying homocysteine concentrations to assess in vitro effects.
Main Results:
- Cardiac G(s) protein was significantly downregulated (to 46% of control) in Hhcy mouse hearts.
- Intracellular G(i) protein levels remained unchanged in Hhcy mouse hearts.
- Homocysteine treatment in HL-1 cells did not result in detectable differential G(s) or G(i) expression.
Conclusions:
- Hyperhomocysteinemia leads to downregulation of cardiac G(s) protein in vivo.
- Homocysteine does not appear to act as a direct agonist to alter G protein content in cardiomyocytes.
- The observed G protein changes likely result from indirect in vivo effects of homocysteine.
Abstract:
High plasma homocysteine levels are a known risk factor in heart failure and sudden cardiac death. The G proteins, G(s) (stimulatory) and G(i) (inhibitory), are involved in calcium regulation; overexpression has pathological consequences. The aims of this study were to examine the differential expression of G(s) G protein and G(i) in the hearts of hyperhomocysteinemic (Hhcy) mice, and to determine if homocysteine (Hcy) acts as an agonist in cell culture to mediate the change in G protein isoforms. To create Hhcy, heterozygous cystathionine-beta-synthase (CBS) knockout (KO) mice were used. Mice were sacrificed, hearts were excised, cardiac tissue homogenates were prepared, and Western blots were performed. The results suggested that G(s) G protein was downregulated in cardiac tissue of heterozygous CBS KO mice to 46% that of control hearts. However, the intracellular G(i) G protein content remained the same in heterozygous CBS KO mice. Transformed cardiomyocyte HL-1 cells were treated with varying concentrations of homocysteine. The results suggested no detectable differential G(s) and G(i) expression. This suggested that Hcy did not act as an agonist in vitro to alter G protein content, but that Hcy produced some other in vivo effects to incur these results.
