Effect of hyperhomocysteinemia on rat cardiac sarcoplasmic reticulum
Zuzana Tatarkova1, Maria Bencurova1, Jan Lehotsky1
1Department of Medical Biochemistry, Jessenius Faculty of Medicine, Comenius University in Bratislava, Mala Hora 4D, 036 01, Martin, Slovakia.
Insights
High homocysteine (Hcy) levels impair heart function by altering calcium handling proteins in the sarcoplasmic reticulum (SR). This study reveals reduced SR Ca2+-handling proteins contribute to cardiac dysfunction in hyperhomocysteinemia (HHcy).
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Elevated plasma homocysteine (Hcy) is a known cardiovascular disease risk factor.
- The precise mechanisms linking hyperhomocysteinemia (HHcy) to cardiac dysfunction remain unclear.
- The sarcoplasmic reticulum (SR) plays a critical role in cardiac muscle contraction and relaxation.
Purpose of the Study:
- To investigate the role of the sarcoplasmic reticulum in cardiac dysfunction associated with HHcy.
- To determine how HHcy affects the expression and function of SR Ca2+-handling proteins.
- To assess the contribution of oxidative stress within the SR to HHcy-induced cardiac impairment.
Main Methods:
- Induction of HHcy in a rodent model via subcutaneous injection of Hcy.
- Assessment of cardiac contractile function by measuring left ventricular pressure and relaxation rates.
- Quantification of SR Ca2+-handling protein levels (SERCA2, calsequestrin, histidine-rich calcium-binding protein, phospholamban) using biochemical assays.
- Evaluation of SR oxidative stress markers.
Main Results:
- HHcy significantly reduced developed left ventricular pressure and the maximum rate of ventricular relaxation.
- Abundances of SR Ca2+-handling proteins, including SERCA2, calsequestrin, and histidine-rich calcium-binding protein, were significantly decreased.
- The ratio of phospholamban to SERCA2 (PLN:SERCA2) increased, inhibiting SERCA2 activity at low calcium concentrations.
- No significant increase in oxidative stress was observed within the SR.
Conclusions:
- Disturbances in SR Ca2+ handling, driven by altered SR protein content, contribute to impaired cardiac contractility in HHcy.
- Reduced SERCA2 activity due to an elevated PLN:SERCA2 ratio is a key mechanism.
- Oxidative damage within the SR is not the primary cause of cardiac dysfunction in this HHcy model.
Abstract:
Increased concentration of plasma homocysteine (Hcy) is an independent risk factor of cardiovascular disease, yet the mechanism by which hyperhomocysteinemia (HHcy) causes cardiac dysfunction is largely unknown. The aim of present study was to investigate the contribution of sarcoplasmic reticulum to impaired cardiac contractile function in HHCy. HHcy-induced by subcutaneous injection of Hcy (0.45 μmol/g of body weight) twice a day for a period of 2 weeks resulted in significant decrease in developed left ventricular pressure and maximum rate of ventricular relaxation. Our results show that abundances of SR Ca2+-handling proteins, Ca2+-ATPase (SERCA2), calsequestrin and histidine-rich calcium-binding protein are significantly reduced while the content of phospholamban is unchanged. Moreover, we found that increased PLN:SERCA2 ratio results in the inhibition of SERCA2 activity at low free Ca2+ concentrations. We further discovered that HHcy is not associated with increased oxidative stress in SR. Taken together, these findings suggest that disturbances in SR Ca2+ handling, caused by altered protein contents but not oxidative damage, may contribute to impaired cardiac contractility in HHcy.
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