Hypertension HYP DEPRESSED CORIN LEVELS INDICATE EARLY SYSTOLIC DYSFUNCTION BEFORE INCREASES OF ANP/BNP AND HEART FAILURE DEVELOPMENT Corin expression and systolic dysfunction HYPE201506300 HYPE201506300 10.1161/HYPERTENSIONAHA.115.06300 67 02/01/16 2 Kuo Denise 214-706-1565 214-706-1565 Granger, Joey University of Mississippi Medical Center Dr. Guy L. Reed glreed@uthsc.edu Dr. University of Tennessee Health Science Center 956 Court Avenue Memphis Tennessee 38163 UNITED STATES 901-448-5752 901-448-1666 21403 Ranjana Tripathi University of Tennessee Health Science Center, Memphis, Tennessee rtripath@uthsc.edu 295467 Dong Wang University of Tennessee Health Science Center dwang16@uthsc.edu 117699 Ryan D. Sullivan University of Tennessee Health Science Center rsulli10@uthsc.edu 155423 Tai-Hwang M. Fan University of Tennessee Health Science Center tfan1@uthsc.edu 155422 Inna Gladysheva University of Tennessee Health Science Cenyet igladysh@uthsc.edu 26623 Guy L. Reed University of Tennessee Health Science Center glreed@uthsc.edu 21403 08/14/2015 08/14/2015 08/28/2015 11/18/2015 11/19/2015 01/13/2016 Original Article Basic ANP BNP Corin dilated cardiomyopathy and heart failure natriuretic peptides Dilated cardiomyopathy is a major cause of heart failure that affects millions. Corin cleaves and biologically activates pro-atrial natriuretic peptide (pro-ANP) and pro-B-type natriuretic peptide (pro-BNP). High corin levels reduce the development of systolic dysfunction and heart failure in experimental dilated cardiomyopathy. Yet, patients with significant heart failure unexpectedly show low corin levels with high plasma ANP/BNP levels. Therefore, we examined the relationship between cardiac corin expression, ANP/BNP levels and the stages of heart failure. We used a well-established dilated cardiomyopathy model to evaluate gene and protein expression as mice longitudinally developed Stages A-D heart failure. Cardiac systolic function (ejection fraction) continuously declined over time (P<0.001). Cardiac corin transcripts were decreased at early Stage B heart failure and remained low through Stages C-D (P<0.001). Cardiac corin levels were positively correlated with systolic function (r=0.96, P=0.003) and inversely with lung water (r=-0.92, P=0.001). In contrast, cardiac pro-ANP/BNP transcripts increased later (Stage C-D) and plasma levels rose only with terminal heart failure (Stage D, P<0.001). Immunoreactive plasma ANP and BNP levels were positively associated with plasma cyclic guanosine monophosphate (cGMP) levels (r=0.82, P=0.01 & r=0.8, P=0.02 respectively). In experimental dilated cardiomyopathy, corin levels declined early with progressive systolic dysfunction before the development of heart failure, while significant increases in plasma ANP, BNP and cGMP levels were found only in later Stage (C, D) heart failure. This dyssynchrony in expression of corin vs. ANP/BNP may impair cleavage-activation of pro-natriuretic peptides and thereby promote the transition from earlier to later stage heart failure. 0 0 0 3 3 no yes HYP_HYPE201506300.xml HYP_HYPE201506300_file1.docx

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HYP_HYPE201506300_supp1.docx HYP_HYPE201506300_merge.pdf HYP_HYPE201506300_Fan_155422_disclosure.pdf HYP_HYPE201506300_Fan_155422_copyright.pdf HYP_HYPE201506300_Sullivan_155423_disclosure.pdf HYP_HYPE201506300_Sullivan_155423_copyright.pdf HYP_HYPE201506300_Reed_21403_disclosure.pdf HYP_HYPE201506300_Reed_21403_copyright.pdf HYP_HYPE201506300_Gladysheva_26623_disclosure.pdf HYP_HYPE201506300_Gladysheva_26623_copyright.pdf HYP_HYPE201506300_Wang_117699_disclosure.pdf HYP_HYPE201506300_Wang_117699_copyright.pdf HYP_HYPE201506300_Tripathi_295467_disclosure.pdf HYP_HYPE201506300_Tripathi_295467_copyright.pdf figures - fit in 2 col. Funding: Howard Hughes Medical Institute (HHMI): No National Institutes of Health (NIH): Yes Not applicable for this manuscript: No Other: No Wellcome Trust: No Subject Codes: [10012] Animal Models of Human Disease [10015] Biomarkers [10035] Mechanisms [10094] Heart Failure dkuo