Transgenic model of heart failure
AssigneesThe General Hospital Corporation, Ohio University, Presidents and Fellows of Harvard College
InventorsCharles C. Homcy, Stephen F. Vatner, Thomas Wagner, Yoshihiro Ishikawa
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Abstract
The present invention relates to transgenic models of heart failure and, more particularly, to transgenic animals and methods for testing the usefulness of chemical compounds in treating or preventing heart failure. A transgenic mouse was developed wherein Gsα is selectively overexpressed approximately three-fold in the heart. Although steady state adenylyl cyclase activities are not altered, both the percent of agonist high affinity β-adrenergic receptors as well as the rate of catalyst activation are increased. In addition, physiological and pathological studies revealed that chronically-facilitated sympathetic stimulation causes adverse cardiac effects.
Claims24
A transgenic mouse from 8 to 16.8 months of age displaying manifestations of heart failure selected from the group consisting of (a) shortness of breath relative to a control mouse, (b) pitting edema relative to a control mouse, (c) an enlarged tender liver relative to a control mouse, (d) engorged neck veins relative to a control mouse, and (e) pulmonary rates relative to a control mouse, wherein the genome of said mouse comprises a murine α-myosin heavy chain gene promoter operably linked to a nucleotide sequence encoding Gsα MRNA, and expresses Gsα mRNA in its cardiac tissue at a level that is at least 3-fold higher than in cardiac tissue of a control mouse.
A transgenic mouse from 8 to 16.8 months of age displaying manifestations of heart failure selected from the group consisting of (a) shortness of breath relative to a control mouse, (b) pitting edema relative to a control mouse, (c) an enlarged tender liver relative to a control mouse, (d) engorged neck veins relative to a control mouse, and (e) pulmonary rates relative to a control mouse, wherein said mouse expresses GSα mRNA, in its cardiac tissue at a level which is at least 3-fold higher than in cardiac tissue of a control mouse, wherein the genome of said mouse contains a murine α-myosin heavy chain gene promoter element operably linked to a nucleotide sequence encoding a GSα protein.
A method for producing a transgenic mouse expressing Gsα mRNA in cardiac tissue, said method comprising:
- a) introducing into an embryonal cell of a mouse a murine α-myosin heavy chain gene promoter operably linked to a nucleotide sequence encoding a Gsα protein;
- b) transplanting the transgenic embryonal target cell formed thereby into a recipient female parent;
- and
- c) identifying at least one transgenic offspring containing said nucleotide sequence in said offspring's genome, wherein at from 8 to 16.8 months of age said offspring displays manifestations of heart failure selected from the group consisting of (a) shortness of breath relative to a control mouse, (b) pitting edema relative to a control mouse, (c) an enlarged tender liver relative to a control mouse, (d) engorged neck veins relative to a control mouse, and (e) pulmonary rates relative to a control mouse, and expresses Gsα mRNA in its cardiac tissue at a level which is at least 3-fold higher than in cardiac tissue of a control offspring.
A method for producing a transgenic mouse expressing GSα mRNA in cardiac tissue, said method comprising:
- a) introducing into an embryonal cell of a mouse a murine α-myosin heavy chain gene promoter operably linked to a nucleotide sequence encoding a GSα protein, wherein said promoter is capable of directing the expression of said nucleotide sequence encoding a GSα protein in a cardiac-specific manner;
- b) transplanting the transgenic embryonal target cell formed thereby into a recipient female parent;
- and
- c) identifying at least one transgenic offspring containing said nucleotide sequence in said offspring's genome, wherein at from 8 to 16.8 months of age said offspring displays manifestations of heart failure selected from the group consisting of (a) shortness of breath relative to a control mouse, (b) pitting edema relative to a control mouse, (c) an enlarged tender liver relative to a control mouse, (d) engorged neck veins relative to a control mouse, and (e) pulmonary rates relative to a control mouse, and expresses GSα mRNA in its cardiac tissue at a level which is at least 3-fold higher than in cardiac tissue of a control offspring.
A method for screening compounds for the ability to prevent or treat the manifestations of heart failure in a mouse, comprising:
- a) providing a transgenic mouse from 8 to 16.8 months of age displaying manifestations of heart failure selected from the group consisting of (a) shortness of breath relative to a control mouse, (b) pitting edema relative to a control mouse, (c) an enlarged tender liver relative to a control mouse, (d) engorged neck veins relative to a control mouse, and (e) pulmonary rales relative to a control mouse, wherein the genome of said mouse comprises a murine α-myosin heavy chain gene promoter operably linked to a nucleotide sequence encoding Gsα mRNA, and expresses Gsα mRNA in its cardiac tissue at a level which is at least 3-fold higher than in cardiac tissue of a control mouse;
- b) administering a compound to said mouse;
- and
- c) measuring an improvement in the physiologic function of the heart of said mouse and thereby identifying a compound as therapeutic.
A transgenic mouse from 10.1 to 10.5 months of age displaying manifestations of heart failure selected from the group consisting of (a) shortness of breath relative to a control mouse, (b) pitting edema relative to a control mouse, (c) an enlarged tender liver relative to a control mouse, (d) engorged neck veins relative to a control mouse, and (e) pulmonary rales relative to a control mouse, wherein the genome of said mouse comprises a murine α-myosin heavy chain gene promoter operably linked to a nucleotide sequence encoding Gsα mRNA, and expresses Gsα mRNA in its cardiac tissue at a level that is at least 3-fold higher than in cardiac tissue of a control mouse.
A transgenic mouse from 8 to 16.8 months of age displaying manifestations of heart failure selected from the group consisting of (a) shortness of breath relative to a control mouse, (b) pitting edema relative to a control mouse, (c) an enlarged tender liver relative to a control mouse, (d) engorged neck veins relative to a control mouse, and (e) pulmonary rales relative to a control mouse, wherein the genome of said mouse comprises a rat α-myosin heavy chain gene promoter operably linked to a nucleotide sequence encoding the short isoform of Gsα mRNA, and expresses Gsα mRNA in its cardiac tissue at a level that is at least 3-fold higher than in cardiac tissue of a control mouse.
Dependencies are inferred from the claim text.