Molecular Magnetic Resonance Imaging Visualizes Nitric Oxide Dynamics in a Mouse Model of Acute Myocardial Inflammation.

Abstract

Nitric oxide (NO) is an essential signaling molecule that appears early in inflammation and persists in chronic diseases, making it a promising biomarker for early detection and treatment monitoring. Although transient NO production supports immune defense, sustained elevations lead to nitrosative stress, tissue injury, and accelerated disease progression. However, NO's short half-life and deep-tissue localization make noninvasive detection challenging. Current diagnostic methods lack combined sensitivity, specificity, and spatial resolution needed to effectively image NO. To address these challenges, we developed a manganese porphyrin-based magnetic resonance imaging (MRI) contrast agent, MnTPPSDiaminotoluene, that selectively detects NO. Acute, reversible myocardial inflammation was induced in mice using isoproterenol (ISO), and the contrast agent was administered at various time points following injury. Cardiac MRI was conducted and validated through biochemical assays of tissue NO levels, immunoblotting, histopathology, and echocardiography. ISO-treated mice exhibited significantly greaterreduction (i.e., greater contrast) compared to sham mice for up to 10 days following MnTPPSDiaminotoluene administration. Importantly, MRI detected a peak myocardial NO level within 3 days postinjury, returning to baseline by day 7. This temporal pattern matched immune cell infiltration and was corroborated by an elevated level of myocardial nitrotyrosine, indicating NO-derived peroxynitrite and nitrosative stress. Mild interstitial fibrosis developed, peaking at day 7, while cardiomyocyte hypertrophy and elevated ejection fraction normalized by day 21. Together, these findings demonstrate that this NO-activatable MRI contrast agent enables direct imaging of NO overproduction, providing a tool for studying inflammation and advancing anti-inflammatory therapeutic development.