Early cardiac dysfunction is rescued by upregulation of SERCA2a pump activity in a rat model of metabolic syndrome

Abstract

In early stage, metabolic syndrome primarily disturbs SERCA2a function in the heart, but consequential haemodynamic dysfunction is prevented by upregulation of SERCA2a protein level and phosphorylation pathways regulating PLB. However, this compensated state is very vulnerable to a further decline in SERCA2a function.

Ca2+ mishandling and cardiac dysfunction in obesity and insulin resistance: Role of oxidative stress

“…In contrast, in a rat model of obesity and IR induced by a diet including sucrose and condensed milk, it was found that decreased SERCA2a activity correlates with its low expression, as well as increased expression and decreased phosphorylation of PLN [89]. Miklos and coworkers using fructose-fed rats showed that despite a slowed decay of ES Ca 2+ transients and depressed SERCA2a function, expression of SERCA2a and PLN phosphorylation are increased [88]. Interestingly, they did not observe alterations in the function of isolated working hearts, thus suggesting that decreased SERCA2a activity may precede cardiac dysfunction and that increased expression of SERCA2a may represent a compensatory mechanism to prevent impaired cardiac function.…”

“…Impaired relaxation accompanied by a prolonged decay of electrically stimulated (ES) Ca 2+ transients in ventricular myocytes is an important feature of obesity and IR-related cardiomyopathy [15,16,48,50,52,85,88]. Therefore, the potential role of key proteins involved in cytosolic Ca 2+ removal (e.g., SERCA2a and NCX) has been of particular interest in finding a mechanistic explanation for impaired cardiac relaxation in obesity and IR.…”

Abnormal amounts of intracellular calcium regulatory proteins in SHRSP.Z-Leprfa/IzmDmcr rats with metabolic syndrome and cardiac dysfunction

“…In contrast, there is considerable controversy regarding the amount of PLB, which has been reported to be increased in diabetes (Zhong et al 2003) and obesity (Relling et al 2006), decreased in obesity (Ceylan-Isik et al 2011), and preserved in hypertension (Boknik et al 2001), diabetes (Bai et al 2012;Basu et al 2009;Zhong et al 2003), heart failure (Sande et al 2002), and insulinresistance (Miklos et al 2012). In contrast, a decreased amount of Ser 16 -phosphorylated PLB has been widely shown in animal models of hypertension (Boknik et al 2001), diet-induced insulinresistance (Mellor et al 2012), obesity (Ceylan-Isik et al 2011), diabetes (Zhong et al 2003v;Rodrigues et al 2011), and heart failure (Sande et al 2002), while there have been few reports describing an increased phosphorylated PLB amount in dietinduced insulin resistance (Miklos et al 2012). Since PLB monomers negatively regulate Ca 2+ reuptake into the SR by SERCA and this process is reversed by phosphorylation at Ser 16 , decreased phosphorylated PLB amounts in SHRSP fatty rats may have important implications for regulation of SERCA by PLB, leading to the development of cardiac dysfunction.…”

“…A decreased amount of SERCA2a in cardiomyocytes has been widely shown in many disease conditions, such as hypertension (Boknik et al 2001), obesity (Ceylan-Isik et al 2011), insulinresistance (Mellor et al 2012), and diabetes (Zhong et al 2003;Basu et al 2009;Rodrigues et al 2011;Bai et al 2012), while some studies have reported an enhanced amount in diet-induced insulinresistance and obesity (Relling et al 2006;Miklos et al 2012). In contrast, there is considerable controversy regarding the amount of PLB, which has been reported to be increased in diabetes (Zhong et al 2003) and obesity (Relling et al 2006), decreased in obesity (Ceylan-Isik et al 2011), and preserved in hypertension (Boknik et al 2001), diabetes (Bai et al 2012;Basu et al 2009;Zhong et al 2003), heart failure (Sande et al 2002), and insulinresistance (Miklos et al 2012).…”

“…Thus, changes in the amounts of these intracellular Ca 2+ regulatory proteins, leading to abnormal intracellular Ca 2+ homeostasis, are relevant to cardiac muscle physiology and pathology (Periasamy et al 2008;Glaves et al 2011). However, there is still controversy as to whether SERCA and PLB protein amounts are altered in lifestyle-related diseases with cardiac dysfunction (Boknik et al 2001;Sande et al 2002;Zhong et al 2003;Li et al 2005;Relling et al 2006;Connelly et al 2007;Yao et al 2009;Ceylan-Isik et al 2011;Rodrigues et al 2011;Bai et al 2012;Dupont et al 2012;Mellor et al 2012;Miklos et al 2012). Furthermore, although PLB is known to exist in oligomeric and monomeric forms, with the monomeric form being the active species that regulates Ca 2+ transport (Periasamy et al 2008), there have been few studies of changes in the amount of each form in disease conditions.…”