Interplay of Iron and Hydrogen Sulfide in Pathophysiology of Vascular Damage

Abstract

Hydrogen sulfide (H₂S) and iron are fundamental regulators of redox biology, exerting opposing influences on oxidative stress and vascular homeostasis, yet their mechanistic interplay remains unresolved. This dissertation addresses this gap through a series of studies spanning molecular, mitochondrial, cellular, and whole-animal levels. The molecular basis of H₂S–iron interactions in vascular smooth muscle cells was defined, demonstrating that endogenous H₂S upregulates ferritin expression, balances apoptosis–autophagy signaling, and protects against iron overload–induced cellular dysfunction. These findings were then extended to mitochondrial physiology, showing that CSE-derived H₂S safeguards mitochondrial respiration, spare respiratory capacity, and membrane potential under iron stress, thereby enhancing cellular resilience. To enable accurate translational assessment, a high-performance liquid chromatography method using a methylene blue/methylene green (MBMG) system was developed, establishing a robust, sensitive, and stable platform for plasma H₂S quantification with broad research applicability. Applying this method in murine models of acute iron overload demonstrated that CSE deficiency led to impaired ferritin upregulation, increased vascular iron deposition, elastin degradation, inflammatory remodeling, and severe vasomotor dysfunction—effects that were mitigated in wild-type mice via compensatory CSE/H₂S induction. Collectively, these studies establish a continuum of evidence linking H₂S to iron metabolism and vascular adaptation, from cellular and mitochondrial mechanisms to systemic physiology. By integrating conceptual review, mechanistic cell studies, methodological innovation, and translational animal models, this thesis identifies endogenous H₂S as both a biomarker and a therapeutic target for iron-related vascular disease.