Abstract-Angiotensin II-induced cardiac damage is associated with oxidative stress-dependent mitochondrial dysfunction.Caloric restriction (CR), a dietary regimen that increases mitochondrial activity and cellular stress resistance, could provide protection. We tested that hypothesis in double transgenic rats harboring human renin and angiotensinogen genes (dTGRs). CR (60% of energy intake for 4 weeks) decreased mortality in dTGRs. CR ameliorated angiotensin II-induced cardiomyocyte hypertrophy, vascular inflammation, cardiac damage and fibrosis, cardiomyocyte apoptosis, and cardiac atrial natriuretic peptide mRNA overexpression. The effects were blood pressure independent and were linked to increased endoplasmic reticulum stress, autophagy, serum adiponectin level, and 5Ј AMP-activated protein kinase phosphorylation. CR decreased cardiac p38 phosphorylation, nitrotyrosine expression, and serum insulin-like growth factor 1 levels. Mitochondria from dTGR hearts showed clustered mitochondrial patterns, decreased numbers, and volume fractions but increased trans-sectional areas. All of these effects were reduced in CR dTGRs. Mitochondrial proteomic profiling identified 43 dTGR proteins and 42 Sprague-Dawley proteins, of which 29 proteins were in common in response to CR. We identified 7 proteins in CR dTGRs that were not found in control dTGRs. In contrast, 6 mitochondrial proteins were identified from dTGRs that were not detected in any other group. Gene ontology annotations with the Panther protein classification system revealed downregulation of cytoskeletal proteins and enzyme modulators and upregulation of oxidoreductase activity in dTGRs. CR provides powerful, blood pressure-independent, protection against angiotensin II-induced mitochondrial remodeling and cardiac hypertrophy. Key Words: hypertension Ⅲ hypertrophy Ⅲ caloric restriction Ⅲ renin-angiotensin system Ⅲ mitochondria Ⅲ oxidative stress T he normal adult heart mainly uses free fatty acids for energy. 1 In heart failure, a shift toward increased glycolysis and glucose oxidation takes place. 2 Metabolic remodeling and impaired substrate use contribute to cardiac dysfunction and participate in the transition of cardiac hypertrophy to heart failure. [1][2][3] Mitochondria are the major site of substrate oxidation. 4 Bugger et al 5 used mitochondrial proteome profiling and found numerous changes in mitochondrial protein levels in rats with pressure overload-induced heart failure. They also demonstrated that the defect found in cardiac oxidative capacity was attributed, at least in part, to a mitochondrial defect downstream of substrate-specific pathways. 5 Oxidative stress causes direct and irreversible oxidative damage to macromolecules and disrupts several key redoxdependent signal transduction pathways in the arterial wall. 6 Angiotensin (Ang) II induces reactive-oxygen species (ROS) formation via Ang II type 1 receptor stimulation through a protein kinase C-dependent mechanism. 7 Vascular NADPH oxidases catalyze the transfer of electrons from the c...