Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Right Ventricular Dysfunction After Pressure Overload


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Collapse abstract
Right ventricular (RV) contractile failure from acute RV pressure overload is an important cause of morbidity and mortality in conditions such as massive pulmonary embolism, hypoxic pulmonary vasoconstriction, and following cardiopulmonary bypass and cardiac transplantation. The applicant previously demonstrated that intrinsic RV contractile function is depressed following a brief period of pressure overload, even after restoration of normal loading conditions. The overall purpose of the proposed research is to determine the mechanism of impaired RV contractile function following acute RV pressure overload. RV dysfunction following pressure overload is qualitatively similar to left ventricular stunning after ischemia-reperfusion, and to skeletal muscle dysfunction after strenuous exercise; these have been hypothesized to result from proteolysis of myofibrillar or cytoskeletal proteins by the calcium-sensitive cysteine protease calpain, or from degradation of the extracellular collagen matrix. Therefore, we plan to test the following hypotheses: #1. RV dysfunction from acute RV pressure overload is associated with and temporally related to proteolytic degradation of myofibrillar proteins, cytoskeletal proteins, and/or the extracellular collagen matrix (ECM). #2. Such proteolytic degradation is manifested by alterations in myofibrillar ATPase activity, disruption of myocardial sarcomere architecture, and or morphologic alterations in the extracellular collagen weave. #3. Degradation of myofibrillar proteins, cytoskeletal proteins, and or the ECM is caused by stress-related activation of calpain and/or of matrix metalloproteinases (MMPs). We plan to determine whether calpain and/or MMPs are activated during acute RV pressure overload, and whether RV dysfunction following acute RV pressure overload can be prevented by specific inhibitors of calpain or MMPs; use 1D and 2D polyacrylamide gel electrophoresis (PAGE), Western blotting and mass spectrometry/peptide fingerprinting to determine the time course of degradation and/or phosphorylation of major myofibrillar and cytoskeletal proteins during acute RV pressure overload; measure changes in RV myofibrillar ATPase activity; and assess myocardial ultrastructure following acute pressure overload. Even if the hypothesized mechanism is not confirmed, the methods employed (so-called proteomics) are likely to identify other potential mechanisms of RV contractile dysfunction, and will contribute to the development of a more complete 2D-PAGE map of porcine myocardial proteins.
Collapse sponsor award id
R01HL068606

Collapse Time 
Collapse start date
2003-07-01
Collapse end date
2008-06-30

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