Rochester, MN, United States
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Ichiki T.,Cardiorenal Research Laboratory | Huntley B.K.,Cardiorenal Research Laboratory | Heublein D.M.,Cardiorenal Research Laboratory | Sandberg S.M.,Cardiorenal Research Laboratory | And 4 more authors.
Clinical Chemistry | Year: 2011

BACKGROUND: B-type natriuretic peptide (BNP), which is activated in heart failure (HF), is processed to an active form by corin. The corin gene is expressed in the human heart and kidney, but corin protein expression in the heart, kidney, and circulation, along with whether proBNP is processed by circulating corin, remains unknown. METHODS: We examined corin protein expression by immunostaining and Western blot in human heart and kidney, and we assessed the circulating corin concentration by ELISA. We examined histidine-tagged (Histag) proBNP1-108 processing in serum and plasma by immunoprecipitation and Western blot and sequenced the processed form. RESULTS: Normal human heart and kidney displayed the presence of corin, especially in cells around the vasculature. Both corin and proBNP1-108 were present in the plasma of healthy human subjects, with circulating corin significantly higher in men than women (P < 0.0001) and a positive correlation of corin to age (P<0.0497, r<0.27). In fresh normal plasma and serum, His-tag proBNP1-108 was processed to a lower molecular weight form confirmed to be BNP. Processed BNP was higher in men than women (P<0.041) and was positively correlated to plasma corin concentrations (P<0.041, r<0.65). CONCLUSIONS: Our results support the concept that proBNP1-108 may be processed outside of the heart in the circulation where the proprotein convertase is present. Moreover, sex may impact this process, since corin concentrations are higher in men. These findings\ may have important physiologic and pathophysiologic implications for the proBNP/corin system in the human. © 2010 American Association for Clinical Chemistry.


Gruson D.,Catholic University of Louvain | Buglioni A.,Cardiorenal Research Laboratory | Burnett J.C.,Cardiorenal Research Laboratory
Clinica Chimica Acta | Year: 2014

Biomarkers play an important role for the diagnosis and prognosis of heart failure (HF), a disease with high morbidity and mortality as well as a huge impact on healthcare budgets. Parathyroid hormone (PTH) is a major systemic calcium-regulating hormone and an important regulator of bone and mineral homeostasis. PTH testing is important for differential diagnosis of calcemia related disorders and for the management of patients with chronic kidney disease. As secondary hyperparathyroidism has been evidenced in HF patients, PTH testing might be relevant in HF patients for risk stratification and more personalized selection of treatment. © 2014.


Chen H.H.,Cardiorenal Research Laboratory | Glockner J.F.,Mayo Medical School | Schirger J.A.,Cardiorenal Research Laboratory | Cataliotti A.,Cardiorenal Research Laboratory | And 2 more authors.
Journal of the American College of Cardiology | Year: 2012

Objectives: The purpose of the present study was to translate our laboratory investigations to establish safety and efficacy of 8 weeks of chronic SC B-type natriuretic peptide (BNP) administration in human Stage C heart failure (HF). Background: B-Type natriuretic peptide is a cardiac hormone with vasodilating, natriuretic, renin-angiotensin inhibiting, and lusitropic properties. We have previously demonstrated that chronic cardiac hormone replacement with subcutaneous (SC) administration of BNP in experimental HF resulted in improved cardiovascular function. Methods: We pe rformed a randomized double-blind placebo-controlled proof of concept study comparing 8 weeks of SC BNP (10 μg/kg bid) (n = 20) with placebo (n = 20) in patients with ejection fraction <35% and New York Heart Association functional class II to III HF. Primary outcomes were left ventricular (LV) volumes and LV mass determined by cardiac magnetic resonance imaging. Secondary outcomes include LV filling pressure by Doppler echo, humoral function, and renal function. Results: Eight weeks of chronic SC BNP resulted in a greater reduction of LV systolic and diastolic volume index and LV mass index as compared with placebo. There was a significantly greater improvement of Minnesota Living with Heart Failure score, LV filling pressure as demonstrated by the reductions of E/e' ratio, and decrease in left atrial volume index as compared with placebo. Glomerular filtration rate was preserved with SC BNP, as was the ability to activate plasma 3′,5′-cyclic guanosine monophosphate (p < 0.05 vs. placebo). Conclusions: In this pilot proof of concept study, chronic protein therapy with SC BNP improved LV remodeling, LV filling pressure, and Minnesota Living with Heart Failure score in patients with stable systolic HF on optimal therapy. Renin-angiotensin was suppressed, and glomerular filtration rate was preserved. Subcutaneous BNP represents a novel, safe, and efficacious protein therapeutic strategy in human HF. Further studies are warranted to determine whether these physiologic observations can be translated into improved clinical outcomes and ultimately delay the progression of HF. (Cardiac Hormone Replacement With BNP in Heart Failure: A Novel Therapeutic Strategy; NCT00252187) © 2012 American College of Cardiology Foundation.


McKie P.M.,Mayo Medical School | Ichiki T.,Cardiorenal Research Laboratory | Burnett Jr. J.C.,Cardiorenal Research Laboratory
Current Hypertension Reports | Year: 2012

The natriuretic peptides, specifically atrial natriuretic peptide (ANP), are increasingly recognized to play a fundamental role in blood pressure (BP) regulation. This role in BP regulation reflects the pluripotent cardiorenal actions of ANP, which include diuresis, enhancement of renal blood flow and glomerular filtration rate, systemic vasodilatation, suppression of aldosterone, and inhibition of the sympathetic nervous system. These actions of ANP, in addition to recent human studies demonstrating an association of higher plasma ANP with lower risk of hypertension, support the development of an ANP-based therapy for hypertension. M-ANP is a novel ANP-based peptide that is resistant to proteolytic degradation and possesses greater BP-lowering, renal function-enhancing, and aldosterone-suppressing properties than native ANP. In an animal model of hypertension, M-ANP lowers BP via multiple mechanisms, including vasodilatation, diuresis, and inhibition of aldosterone. Importantly, M-ANP enhances both glomerular filtration rate and renal blood flow despite reductions in BP. The pluripotent BP-lowering actions and concomitant enhancement of renal function associated with M-ANP are highly attractive characteristics for an antihypertensive agent and underscore the therapeutic potential of M-ANP. M-ANP currently is heading into clinical testing, which may advance this novel strategy for human hypertension. © 2011 Springer Science+Business Media, LLC.


Ichiki T.,Cardiorenal Research Laboratory | Huntley B.K.,Cardiorenal Research Laboratory | Burnett J.C.,Cardiorenal Research Laboratory
Advances in Clinical Chemistry | Year: 2013

The cardiac hormone, B-type natriuretic peptide (BNP), is one of human natriuretic peptides which possesses cardiorenal protective actions and is used as a therapeutic and a biomarker for heart failure (HF). Its prohormone, proBNP1-108, is processed by the proNPs convertases, corin or furin, to inactive NT-proBNP1-76 and active BNP1-32. Paradoxically, circulating NT-proBNP and BNP are elevated in HF leading to the use of BNP as a sensitive and predictive marker of HF. This paradox may be explained by the "nonspecific" nature of conventional assays and/or a relative deficiency state of "active BNP" as characterized by an increase in inactive proBNP1-108 and a decrease in active BNP1-32. Therefore, understanding the regulation of proBNP1-108 processing and the role of the convertase corin may be important in understanding the physiology of HF. Corin is expressed in heart and kidney and may play an important role in regulating blood pressure and remodeling of the heart. The processing of proBNP1-108 by corin may be controlled by O-linked glycosylation of proBNP1-108. A potential impairment of proBNP1-108 processing in HF may be linked to dysregulation of the convertase corin, which may offer therapeutic opportunities to control proBNP1-108 processing and its activation in HF. © 2013 Elsevier Inc.


McKie P.M.,Cardiorenal Research Laboratory | Sangaralingham S.J.,Cardiorenal Research Laboratory | Burnett Jr. J.C.,Cardiorenal Research Laboratory
Current Heart Failure Reports | Year: 2010

The natriuretic peptide (NP) family consists of structurally similar, although physiologically distinct, peptides that play an important role in cardiorenal homeostasis. CD-NP is a novel chimeric natriuretic peptide developed by the Mayo Clinic, in which the 15-amino acid COOH-terminus of dendroaspis NP is fused to C-type NP. CD-NP is a dual activator of NP receptors A and B, and therefore, possesses the strong antiproliferative and antifibrotic properties of C-type NP with the potent natriuretic, diuretic, and aldosterone-inhibiting properties of dendroaspis NP. CD-NP has favorable cardiorenal properties when compared to recombinant B-type NP (nesiritide), including preservation of glomerular filtration rate with minimal blood pressure-lowering effects. Thus, CD-NP has emerged as an appealing novel therapeutic strategy for heart failure. The endogenous NP system, the development rationale for CD-NP, as well as in vitro, animal, and human studies and future directions will be reviewed. © 2010 Springer Science+Business Media, LLC.


McKie P.M.,Cardiorenal Research Laboratory | Burnett J.C.,Cardiorenal Research Laboratory
Current Heart Failure Reports | Year: 2015

The natriuretic peptide system (NPS) is intimately involved in cardiorenal homeostasis in health, and dysregulation of the NPS plays an important role in the pathophysiology of heart failure (HF). Indeed, the diuretic, vasorelaxation, beneficial remodeling, and potent neurohumoral inhibition of the NPS support the therapeutic development of chronic augmentation of the NPS in symptomatic HF. Further, chronic augmentation of the protective NPS and in early stages of HF may ultimately prevent the progression of HF and reduced subsequent morbidity and mortality. In the current manuscript, we review the rationale for as well as previous and current efforts aimed at chronic therapeutic augmentation of the NPS in HF. © 2014, Springer Science+Business Media New York.


Huntley B.K.,Cardiorenal Research Laboratory | Sandberg S.M.,Cardiorenal Research Laboratory | Heublein D.M.,Cardiorenal Research Laboratory | Jeson Sangaralingham S.,Cardiorenal Research Laboratory | And 2 more authors.
Circulation: Heart Failure | Year: 2015

Background-We have reported that proB-type natriuretic peptide (BNP)-1-108 circulates and is processed to mature BNP1-32 in human blood. Building on these findings, we sought to determine whether proBNP1-108 processed forms in normal circulation are biologically active and stimulate cGMP, and whether proBNP1-108 processing and activity are altered in human heart failure (HF) compared with normal. Because BNP1-32 is deficient whereas proBNP1-108 is abundant in HF, we hypothesize that proBNP1-108 processing and degradation are impaired in HF patients ex vivo. Methods and Results-We measured circulating molecular forms, including BNP1-32, proBNP1-108, and N-terminalproBNP, and all were significantly higher in patients with HF when compared with that in normals. Fresh serum samples from normals or patients with HF were incubated with or without exogenous nonglycosylated proBNP1-108 tagged with 6 C-terminal Histidines to facilitate peptide isolation. His-tag proBNP1-108 was efficiently processed into BNP1-32/3-32 at 5 minutes in normal serum, persisted for 15 minutes, then disappeared. Delayed processing of proBNP1-108 was observed in HF samples, and the degradation pattern differed depending on left ventricular function. The 5-minute processed forms from both normal and HF serums were active and generated cGMP via guanylyl cyclase-A receptors; however, the 180-minute samples were not active. The proBNP1-108 processing enzyme corin and BNP-degrading enzyme dipeptidyl peptidase-4 were reduced in HF versus normal, perhaps contributing to differential BNP metabolism in HF. Conclusions-Exogenous proBNP1-108 is processed into active BNP1-32 and ultimately degraded in normal circulation. The processing and degradation of BNP molecular forms were altered but complete in HF, which may contribute to the pathophysiology of HF. © 2015 American Heart Association, Inc.


Systemic hypertension is a common characteristic in acute heart failure (HF). This increasingly recognized phenotype is commonly associated with renal dysfunction and there is an unmet need for renal enhancing therapies. In a canine model of HF and acute vasoconstrictive hypertension we characterized and compared the cardiorenal actions of M-atrial natriuretic peptide (M-ANP), a novel particulate guanylyl cyclase (pGC) activator, and nitroglycerin, a soluble guanylyl cyclase (sGC) activator. HF was induced by rapid RV pacing (180 beats per minute) for 10 days. On day 11, hypertension was induced by continuous angiotensin II infusion. We characterized the cardiorenal and humoral actions prior to, during, and following intravenous M-ANP (n=7), nitroglycerin (n=7), and vehicle (n=7) infusion. Mean arterial pressure (MAP) was reduced by M-ANP (139 ± 4 to 118 ± 3 mm Hg, P<0.05) and nitroglycerin (137 ± 3 to 116 ± 4 mm Hg, P<0.05); similar findings were recorded for pulmonary wedge pressure (PCWP) with M-ANP (12 ± 2 to 6 ± 2 mm Hg, P<0.05) and nitroglycerin (12 ± 1 to 6 ± 1 mm Hg, P<0.05). M-ANP enhanced renal function with significant increases (P<0.05) in glomerular filtration rate (38 ± 4 to 53 ± 5 mL/min), renal blood flow (132 ± 18 to 236 ± 23 mL/min), and natriuresis (11 ± 4 to 689 ± 37 mEq/min) and also inhibited aldosterone activation (32 ± 3 to 23 ± 2 ng/dL, P<0.05), whereas nitroglycerin had no significant (P>0.05) effects on these renal parameters or aldosterone activation. Our results advance the differential cardiorenal actions of pGC (M-ANP) and sGC (nitroglycerin) mediated cGMP activation. These distinct renal and aldosterone modulating actions make M-ANP an attractive therapeutic for HF with concomitant hypertension, where renal protection is a key therapeutic goal.


Zakeri R.,Cardiorenal Research Laboratory | Burnett J.C.,Cardiorenal Research Laboratory | Sangaralingham S.J.,Cardiorenal Research Laboratory
Clinica Chimica Acta | Year: 2015

The public health and economic burden of heart failure (HF) is staggering and the need for relevant pathophysiologic and clinical biomarkers to advance the field and improve HF therapy remains high. Renal dysfunction is common among HF patients and is associated with increased HF hospitalization and mortality. It is widely recognized that mechanisms contributing to HF pathogenesis include a complex bidirectional interaction between the kidney and heart, encompassed by the term cardiorenal syndrome (CRS). Among a new wave of urinary biomarkers germane to CRS, C-type natriuretic peptide (CNP) has emerged as an innovative biomarker of renal structural and functional impairment in HF and chronic renal disease states. CNP is a hormone, synthesized in the kidney, and is an important regulator of cell proliferation and organ fibrosis. Hypoxia, cytokines and fibrotic growth factors, which are inherent to both cardiac and renal remodeling processes, are among the recognized stimuli for CNP production and release. In this review we aim to highlight current knowledge regarding the biology and pathophysiological correlates of urinary CNP, and its potential clinical utility as a diagnostic and prognostic biomarker in HF and renal disease states. © 2015 Elsevier B.V.

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