Scheme 1.

Signaling pathways that link cardiac ATGL deficiency to oxidative inflammatory stress and increased sGC activity. Impaired PPARα signaling in ATGL deficiency induces cardiac hypertrophy (path 1) that is compensated by increased sGC activity (path 6). Impaired PPARα signaling leads to increased superoxide production by NADPH oxidases (path 2) and augmented expression of inflammatory markers (path 3). Elevated TNFα levels induce expression of cardiac NADPH oxidases via activation of PKC (path 4). Lipid droplet surface-binding proteins directly initiate oxidative and inflammatory processes (path 5). NADPH oxidase-generated superoxide scavenges NO to form ONOO⁻ (path 7). Reduced NO availability induces activation of cardiac sGC. NADPH oxidase-derived superoxide production enhances cardiac hypertrophy and contractile dysfunction (path 8).