Anne-Marie Koop

170 is essential for optimal mitochondrial energy production. 39-41 Defects in cardiolipin content affect complexes I, II, III and IV of the electron transport chain, 42-46 leading to reduced oxidative capacity and increased production of reactive oxygen species. 45-48 Nevertheless, we did not find evidence of impaired mitochondrial function and one may speculate that the reductions in RV cardiolipin content precede a decrease in respiratory capacity due to a dysfunctional mitochondrial inner membrane leading to progressive oxidative stress. In addition to a decreased cardiolipin content, the reduction of (P)UFA’s also affected other lipid major classes. Since in this studymitochondriawere not affected in number and their respiratory capacity for fatty acids, these reductions may be caused by oxidative stress or by reduced levels of common precursor lipids due to decreased uptake of long-chain fatty acids (LCFA). PUFA’s are known to be vulnerable to oxidative stress because of their hydrogen atoms close to multiple double bounds, which are easily taken by hydroxyl radicals. The current study did show initial increases of inducers of oxidative stress, which faded over time. The pattern was also recognized at the level of actual oxidative stress and inflammation, however, these results did not reach statistical significance. We speculate that PUFA’s serve as primary preventive response and enables preservation of anti-oxidant capacity in the pressure overloaded RV. Another explanation may be inadequate uptake of essential lipids in the stressed RV. Diminished levels of CD36, a prominent LCFA transport protein in contracting cardiomyocytes, 49 have previously been observed in LV hyperthrophy and heart failure. 50 In addition, in the LV, adequate lipid turnover mediated by TG- pools has been shown to protect the heart against ceramides, known as inducer of mitochondrial dysfunction and apoptosis, making sufficient lipid availability even more relevant. All this toghether suggests that limited availability of PUFA’s, including cardiolipin, precedes deterioration of RV hemeostasis and function. In the LV, upregulation of NADPH oxidase is known to induce fibrosis by the expression of TGF β 1, 51,52 which is accompanied with diastolic dysfunction. 51 A similar pattern is observed in the current model of RV pressure overload. NADPH oxidase is recognized as activator of oxidative stress. 53,54 In the current study we show upregulation of NAPDH oxidase 2 and 4, without significant upregulation of actual oxidative stress. Although this might be due to lack of sufficient statistical power, this might also imply that in the state of compensated RV dysfunction, activation of oxidative stress is mild and might be balanced by protective mechanisms other than anti-oxidants and proteins. How exactly upregulation of NADPH oxidase is triggered, is yet still unknown. In the diabetic mice heart, growing evidence suggest that NADPH oxidase is stimulated by hyperglyceamia, 55,56 whereas in hypertensive rats NADPH oxidase seems to be indirectly stimulated by systemic and local effects of angiotensin II. 52,57 In pressure overload ventricles, both left 57,58 and right, the exact