Arterial Smooth Muscle Mitochondria Amplify Hydrogen Peroxide Microdomains Functionally Coupled to L-Type Calcium Channels
| Autor: | Madeline Nieves-Cintrón, Manuel F. Navedo, Adriana M. Fresquez, Nathan L. Chaplin, Gregory C. Amberg |
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| Rok vydání: | 2015 |
| Předmět: |
Male
hypertension Calcium Channels L-Type Physiology 1.1 Normal biological development and functioning Clinical Sciences Myocytes Smooth Muscle chemistry.chemical_element Cardiorespiratory Medicine and Haematology Biology Calcium Mitochondrion Muscle Smooth Vascular Article Calcium in biology smooth muscle Rats Sprague-Dawley Membrane Microdomains Underpinning research Vascular calcium channels hypertension myocytes oxidative stress Animals Myocyte L-type calcium channel reactive oxygen species Myocytes Voltage-dependent calcium channel T-type calcium channel Hydrogen Peroxide Cerebral Arteries L-Type Angiotensin II Mitochondria Mitochondria Muscle Rats Cell biology Cardiovascular System & Hematology Biochemistry chemistry Basilar Artery Muscle Smooth Sprague-Dawley Reactive Oxygen Species Cardiology and Cardiovascular Medicine |
| Zdroj: | Circulation research, vol 117, iss 12 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/circresaha.115.306996 |
| Popis: | Rationale: Mitochondria are key integrators of convergent intracellular signaling pathways. Two important second messengers modulated by mitochondria are calcium and reactive oxygen species. To date, coherent mechanisms describing mitochondrial integration of calcium and oxidative signaling in arterial smooth muscle are incomplete. Objective: To address and add clarity to this issue, we tested the hypothesis that mitochondria regulate subplasmalemmal calcium and hydrogen peroxide microdomain signaling in cerebral arterial smooth muscle. Methods and Results: Using an image-based approach, we investigated the impact of mitochondrial regulation of L-type calcium channels on subcellular calcium and reactive oxygen species signaling microdomains in isolated arterial smooth muscle cells. Our single-cell observations were then related experimentally to intact arterial segments and to living animals. We found that subplasmalemmal mitochondrial amplification of hydrogen peroxide microdomain signaling stimulates L-type calcium channels, and that this mechanism strongly impacts the functional capacity of the vasoconstrictor angiotensin II. Importantly, we also found that disrupting this mitochondrial amplification mechanism in vivo normalized arterial function and attenuated the hypertensive response to systemic endothelial dysfunction. Conclusions: From these observations, we conclude that mitochondrial amplification of subplasmalemmal calcium and hydrogen peroxide microdomain signaling is a fundamental mechanism regulating arterial smooth muscle function. As the principle components involved are fairly ubiquitous and positioning of mitochondria near the plasma membrane is not restricted to arterial smooth muscle, this mechanism could occur in many cell types and contribute to pathological elevations of intracellular calcium and increased oxidative stress associated with many diseases. |
| Databáze: | OpenAIRE |
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