Statin treatment increases formation of carbon monoxide and bilirubin in mice: a novel mechanism of in vivo antioxidant protection

Abstract

Heme oxygenase (HO) has a central role in cellular antioxidant defences and vascular protection, and it may mediate pleiotropic actions of drugs used in cardiovascular therapy. We investigated whether long-term use of statins upregulates HO activity and increases carbon monoxide (CO) and bilirubin levels in vivo. Adult FvB mice were given atorvastatin or rosuvastatin (5 mg/kg) daily by i.p. injections for 1, 2, or 3 weeks. HO activity, tissue CO, bilirubin, and antioxidant levels, total plasma bilirubin, and carboxyhemoglobin (COHb) were measured. Fold changes in heart HO activity significantly increased after 1, 2, and 3 weeks of atorvastatin (1.24 +/- 0.06 (p < or = 0.05); 1.29 +/- 0.26 (p < or = 0.03); 1.33 +/- 0.08 (p < 0.01), respectively) and 2 and 3 weeks of rosuvastatin (1.23 +/- 0.20 (p < or = 0.03); 1.63 +/- 0.42 (p < 0.01), respectively). Heart tissue CO and COHb levels also increased after 3 weeks with atorvastatin (1.30 +/- 0.24 (p < or = 0.05); 1.92 +/- 0.17 (p < or = 0.001), respectively) and rosuvastatin (1.47 +/- 0.13 (p < or = 0.004); 1.63 +/- 0.12 (p < or = 0.001), respectively). Significant increases in heart antioxidant levels were observed after statin treatment and corroborated by heart bilirubin content elevations. Antioxidant level increases were abolished by treatment with an HO inhibitor. These findings suggest that the induction of HO and the production of its products, CO and bilirubin, may be a mechanism by which statins exert antioxidant actions and confer cardioprotection in vivo.

Cardiovascular Events as a Function of Serum Bilirubin Levels in a Large, Statin-Treated Cohort

“…Animal studies have reported that statin administration increases heme oxygenase expression in heart and lung tissue, together with an increase in serum bilirubin level. 41,42 Increases in heme oxygenase levels in response to statins have also been identified in human endothelial tissues, 43 and studies in humans show a modest increase in serum bilirubin that is independent of changes in liver enzymes of Ϸ10% to 20% after statin treatment. 44,45 If heme oxygenase stimulation explains some the mechanism of statin efficacy, via bilirubin or other byproducts, and this stimulation is more pronounced in patients with a higher bilirubin level measured before prescription, this could also partially explain the negative relationships with CVD described in the present study.…”

The role of gasotransmitters NO, H2S and CO in myocardial ischaemia/reperfusion injury and cardioprotection by preconditioning, postconditioning and remote conditioning

“…These pathways include those involving NO/GC, ROS and MAPKs. The relevant biosynthetic enzyme, HO, has a central role in cellular antioxidant defence and vascular protection, and it may mediate many of the actions of drugs used in cardiovascular therapy (Muchova et al, 2007). Cardiovascular tissues express HO, which metabolizes haem to form CO. Up-regulation of HO-1 occurs in the heart after stress such as I/R and provides cardioprotection; most evidence indicates that CO is responsible for most of these beneficial effects (Johnson et al, 2004;Peers and Steele, 2012), as it exerts anti-apoptotic and cytoprotective effects (Stein et al, 2012).…”

“…It is now widely recognized that the gasotransmitters NO, along with hydrogen sulphide (H2S) and carbon monoxide (CO), are involved in a multitude of physiological functions (Caliendo et al, 2010;Szabo, 2010;Peers and Steele, 2012). In the cardiovascular system, the regulatory role of NO and H2S includes vasorelaxation, stimulation of angiogenesis and cardioprotection (Szabo, 2010;Coletta et al, 2012), and that of CO includes relaxation of coronary vascular smooth muscle and cardioprotection (Muchova et al, 2007).…”

“…It is now widely recognized that the gasotransmitters NO, along with hydrogen sulphide (H2S) and carbon monoxide (CO), are involved in a multitude of physiological functions (Caliendo et al, 2010;Szabo, 2010;Peers and Steele, 2012). In the cardiovascular system, the regulatory role of NO and H2S includes vasorelaxation, stimulation of angiogenesis and cardioprotection (Szabo, 2010;Coletta et al, 2012), and that of CO includes relaxation of coronary vascular smooth muscle and cardioprotection (Muchova et al, 2007).The synthesis and major metabolic pathways of NO are described in detail elsewhere (Moncada et al, 1997;Pacher et al, 2007;Rassaf et al, 2014), including the current Themed Issue (see Csonka et al, 2015). In brief, NO is produced in most of the mammalian tissues and cells by both enzymic and non-enzymic reactions.…”

“…Cardiovascular tissues express HO, which metabolizes haem to form CO. Up-regulation of HO-1 occurs in the heart after stress such as I/R and provides cardioprotection; most evidence indicates that CO is responsible for most of these beneficial effects (Johnson et al, 2004;Peers and Steele, 2012), as it exerts anti-apoptotic and cytoprotective effects (Stein et al, 2012). CO also has antihypertensive and anti-inflammatory effects (Muchova et al, 2007).Besides the NO, H2S and CO, there are other gasotransmitters, such as hydrogen, methane, as well as some noble gases (He, Xe) that also exert cardioprotective effects. Inhalation of hydrogen gas has been shown to limit infarct size following I/R injury in rat and in canine hearts via opening of mitochondrial KATP channels followed by inhibition of mitochondria permeability transition pore opening (mPTP) (Yoshida et al, 2012).…”