case western reserve university





Joseph C. Miller, PhD

Biochemical Mechanisms of Cell Injury

My research focuses on changes in cell membrane function during the pathogenesis of cell injury. Alterations in phospholipid metabolism, particularly the involvement of calcium and phospholipases, are being studied in models of myocardial cell injury. Isolated cardiac myocytes

and membranes (subcellular fractions) are utilized to investigate the phenomena associated with the progression of cell injury: accumulation of free fatty acids, calcium loading, morphological damage, and ATP depletion. We have demonstrated that hypoxia produces increased fatty acid release and alters alpha adrenergic receptor-stimulated phosphatidylinositol turnover in isolated myocytes. Similar changes have been observed with the beta adrenergic receptor-adenylate cyclase complex. We have demonstrated recently that the protective role effects of dietary fish oils containing omega-3 fatty acids may stem from functional alterations of this adrenergic receptor-effector system within the myocardial cell membrane. Clearly, altered phospholipid metabolism and membrane integrity correlate with the onset of irreversible myocardial injury. Abnormal phospholipase activity, and altered intracellular calcium regulation, underlying several of the hypotheses currently proposed to explain the mechanism of cellular damage during ischemia. A primary goal of my studies is to delineate the biochemical etiology of cellular injury involving several aspects of cell function. By determining the pathogenic mechanism(s) of myocardial cell injury, more specific interventions may be designed to reduce the damage resulting from ischemic or hypoxic episodes.

An integrated battery of analytical biochemical techniques is used to characterize these changes in the various models, including enzyme and receptor analysis, metabolism of radioactive tracers, high-pressure and thin-layer chromatography, and microspectrofluorometry with the intracellular dyes, such as fura-2, for calcium abnormalities. The biological models range from isolated cell cultures to whole animal studies. In addition, we are utilizing experimental pharmacological agents in attempts to prevent the transition of injury from a reversible to an irreversible stage.

Selected References:

JC Miller and PA Weinhold, Cholinephosphotransferase in rat lung: The in vitro synthesis of dipalmitoyl phosphatidylcholine from dipalmitoyl glycerol. J Biol Chem 256:12662-12665, 1981.

O Tone, JC Miller, IM Bell, and SI Rapoport, Regional cerebral palmitate incorporation following transient bilateral carotid occlusion in awake gerbils. Stroke 18:1120-1127, 1987.

JC Miller, JM Gnaedinger, and SI Rapoport, Utilization of plasma fatty acid in rat brain: Distribution of [14C]-palmitate between oxidative and synthetic pathways. J Neurochem 49: 1507-1514, 1987.

RL Jones, JC Miller, HK Hagler, KR Chien, JT Willerson, and LM Buja, Association between inhibition of arachidonic acid release and prevention of calcium loading during ATP depletion in cultured rat cardiac myocytes. Am J Pathology 135:541-556, 1989.

KH Muntz, M Zhao, and JC Miller. Review: Down-regulation of myocardial 13-adrenergic receptors: Receptor subtype selectivity. Circ Res 74:369-375, 1994.


Dept. of Anatomy | 10900 Euclid Ave. | Cleveland, Ohio 44106-4930 | Phone:216.368.2433|
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