SUMOylation as a Stress-Responsive Rheostat in Cardiovascular Disease

SUMOylation is a reversible post-translational modification that regulates protein stability, localization, activity, and protein–protein interactions. In the cardiovascular system, SUMO signaling intersects with oxidative stress, mitochondrial homeostasis, calcium handling, inflammatory activation, and stress-induced transcriptional reprogramming. Here, we review the molecular architecture of the SUMO system and its redox sensitivity and integrate evidence for SUMO-dependent regulation of mitochondrial quality control, metabolic adaptation, inflammatory responses, and regulated cell death. We further examine how these mechanisms contribute to atherosclerosis, myocardial ischemia–reperfusion injury, cardiac remodeling, heart failure, arrhythmia, and pulmonary vascular disease, while distinguishing evidence that is mechanistic, correlative, or contradictory. Based on this evidence, we propose a stress-responsive SUMO rheostat framework in which the functional output of SUMO signaling is shaped not simply by the magnitude of stress, but by the interplay among stress intensity and duration, subcellular compartment, substrate accessibility and abundance, SUMO paralogue composition, enzyme activity, cell identity, and disease stage. These contextual variables can influence which SUMO-regulated substrates are accessible to individual enzymes, where modification occurs, and how long it persists, thereby contributing to divergent functional outcomes under otherwise similar stress conditions. The framework is intended as a conceptual synthesis for reconciling seemingly divergent effects of SUMOylation across cardiovascular diseases rather than as a quantitatively validated stress–SUMO response model. Finally, we discuss the translational challenges and opportunities of moving beyond global modulation of the SUMO pathway toward substrate-selective, enzyme-selective, and cell-targeted therapeutic strategies.