Natriuretic peptide related fragment in cardiovascular disease

Abstract

This disclosure provides an intracellular fragment of natriuretic peptide receptor A (NPRA), referred to herein as soluble natriuretic peptide receptor-related fragment (sNRF). It is shown herein that sNRF causes NP resistance. Based on these observations, methods of treating a cardiovascular disorder by inhibiting the activity of sNRF are disclosed. Assays are provided that use sNRF to screen agents for their ability to increase the biological activity of an NPR, for example agents that increase the sensitivity of NPR for NPs (such as atrial natriuretic peptide, ANP), or that decrease growth factor deleterious effects, or combinations thereof. Also provided are agents identified using the disclosed assays, and methods of using the agents, for example to treat or diagnose a cardiovascular disorder, such as heart failure.

1 . A method of treating cardiovascular disease, comprising significantly decreasing sNRF activity in a cardiac cell, wherein significantly decreasing sNRF activity treats the cardiovascular disease. 
     
     
         2 . The method of  claim 1 , wherein significantly decreasing sNRF activity comprises decreasing expression of an mRNA encoding sNRF in the cell, increasing sensitivity of a natruiuretic peptide receptor (NRP) in the cell for NP, decreasing deleterious growth factor effects, or combinations thereof. 
     
     
         3 . The method of  claim 2 , wherein significantly decreasing expression of the mRNA encoding sNRF comprises contacting the mRNA with an antisense RNA, triple helix molecule, ribozyme, microRNA, or siRNA that recognizes the sNRF mRNA. 
     
     
         4 . The method of  claim 3 , wherein the antisense RNA, triple helix molecule, ribozyme, microRNA, or siRNA that recognizes the sNRF mRNA is complementart to at least 20 contiguous of nucleotides 1-215 of SEQ ID NO: 37. 
     
     
         5 . The method of  claim 4 , wherein decreasing expression of mRNA encoding sNRF comprises contacting the mRNA with one or more of SEQ ID NOS: 14, 16, 18, 20, 22, 24, 26, 28, 30, or 32. 
     
     
         6 . The method of  claim 4 , wherein decreasing expression of mRNA encoding sNRF comprises contacting the mRNA with one or more duplexes formed by SEQ ID NOS: 13 and 14, 15 and 16, 17 and 18, 19 and 20, 21 and 22, 23 and 24, 25 and 26, 27 and 28, 29 and 30, or 31 and 32. 
     
     
         7 . The method of  claim 1 , wherein sNRF is encoded by a nucleic acid molecule comprising at least 95% sequence identity to any of SEQ ID NOS: 3, 5, 37, 39, or 41. 
     
     
         8 . The method of  claim 7 , wherein sNRF is encoded by a nucleic acid molecule consisting of any of SEQ ID NOS: 3, 5, 37, 39 or 41. 
     
     
         9 . The method of  claim 1 , wherein the cardiac cell is a human cardiac cell. 
     
     
         10 . The method of  claim 1 , wherein the cardiac cell is present in a subject, and decreasing activity of sNRF in a cardiac cell comprises administering a therapeutically effective amount of an agent that decreases activity of sNRF in the cardiac cell to the subject. 
     
     
         11 . A method of treating a subject having cardiovascular disease, comprising:
 determining whether the subject has cardiovascular disease or is at an increased risk for developing cardiovascular disease;   administering a therapeutically effective amount of an agent that significantly decreases sNRF activity to a subject having cardiovascular disease or having an increased risk for developing cardiovascular disease, which indicates that the subject can be treated with the agent, thereby treating the cardiovascular disease.   
     
     
         12 . The method of  claim 1 , wherein the cardiovascular disease is angina pectoris; arrhythmia; cardiac fibrosis, congenital cardiovascular disease; coronary artery disease (CAD); dilated cardiomyopathy; heart attack (myocardial infarction); heart failure; hypertrophic cardiomyopathy; systemic hypertension from any cause, edematous disorders caused by liver or renal disease, mitral regurgitation, myocardial tumors, myocarditis, rheumatic fever, Kawasaki disease, Takaysu arteritis, cor pulmonale, primary pulmonary hypertension, amyloidosis, hemachromatosis, toxic effects on the heart due to poisoning, Chaga's disease, heart transplantation, cardiac rejection after heart transplantation, cardiomyopathy of chachexia, arrhythmogenic right ventricular dysplasia, cardiomyopathy of pregnancy, Marfan Syndrome; Turner Syndrome; Loeys-Dietz Syndrome, familial biscuspid aortic valve, or any inherited disorder of the heart or vasculature, or combinations thereof. 
     
     
         13 . The method of  claim 11 , wherein determining whether the subject has cardiovascular disease or is at an increased risk for developing cardiovascular disease comprises determining serum levels of ANP, BNP, or cGMP, wherein a serum level of >50-100 pg/ml for ANP, a serum level of 50-100 pgt/ml for BNP, or a serum level of >8 pg/ml for cGMP, indicates that the subject has cardiovascular disease or is at an increased risk for developing cardiovascular disease. 
     
     
         14 . The method of  claim 1 , wherein the cardiovascular disease results from a desensitized NPRA or increased growth factor deleterious effects. 
     
     
         15 . An isolated protein comprising the sequence of SEQ ID NO: 4, 6, 8, 38, 40 or 42. 
     
     
         16 . An isolated nucleic acid molecule encoding the protein of  claim 15 . 
     
     
         17 . The isolated nucleic acid molecule of  claim 16 , wherein the isolated nucleic acid molecule consists of SEQ ID NO: 3, 5, 7, 37, 39, or 41.