Molecular dissection of compensatory pathways in models of severe heart failure
2015-01
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Molecular dissection of compensatory pathways in models of severe heart failure
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2015-01
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Cardiovascular diseases are the leading cause of death in America, and heart failure (HF) is an important and increasingly difficult to manage disease. HF, a clinical syndrome of impaired heart pump function, has poor prognosis, increasing incidence, and no cure. Clinical treatment guidelines focus on the treatment of symptoms rather than acting to directly restore heart pump function, and better therapeutics are necessary to reverse the course of HF pathology. Normal heart pump function is driven by the release and reuptake of Ca2+ ions from the cytoplasm of cardiac myocytes. In healthy cardiac tissue, transient release of Ca2+ occurs rapidly to trigger contraction, and removal is likewise swift in order to allow the heart to relax and refill with blood for the next beat. In failing myocardium, Ca2+ release is weak and reuptake is slow, which leads to inadequate ejection of blood to the body and poor refilling for the next beat. Over time, this results in the progressive loss of cardiac pump function and, subsequently, worsening quality of life. The protein responsible for most diastolic Ca2+ reuptake to the cardiac sarcoplasmic reticulum (SR) compartment is the SR Ca2+ ATPase, SERCA2a. SERCA2a expression and activity are decreased in failing hearts, and experimental therapeutics are currently under development to restore its activity in humans. We have utilized a mouse model of inducible Serca2 deletion, the Serca2fl/fl mouse, to study the progression of cardiac dysfunction as this key enzyme is lost. Surprisingly, Serca2KO mice survive 7-10 weeks following inducible Serca2 deletion and loss of most SERCA2a protein. The mechanisms by which Serca2KO mice maintain survival for so long with minimal apparent in vivo pathology are not well defined, so we investigated cardiac performance in Serca2KO hearts and mice by several methods. We determined the function of KO hearts outside the body, in the absence of systemic signaling that may be supporting function in vivo, and found that isolated KO hearts had severely impaired function even at short times following gene deletion; we studied adaptive changes in cardiac Ca2+ handling proteins, including SERCA2a, that occur in hibernating mammals between the summer and winter seasons; and we enacted a thorough mechanistic dissection of ß-adrenergic signaling pathways in SERCA2a-depleted hearts. We found that Serca2KO hearts deficient in normal Ca2+ handling remained able to support a significant functional response to adrenergic stimulation, despite the near complete absence of SERCA2a, which is normally a key functional substrate for the adrenergic response. This finding indicated that other targets of adrenergic signaling in SERCA-deficient heart were surprisingly capable of supporting significant pump function despite poor cardiac Ca2+ transport capabilities, and we have identified the myofilament protein, cardiac troponin I (cTnI), as a key component of an intact adrenergic response under pathological Ca2+ handling conditions.
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University of Minnesota Ph.D. dissertation. January 2015. Major: Biochemistry, Molecular Bio, and Biophysics. Advisors: Joseph Metzger, Eric Hendrickson. 1 computer file (PDF); viii, 185 pages.
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Heinis, Frazer. (2015). Molecular dissection of compensatory pathways in models of severe heart failure. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/185607.
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