B-Type Natriuretic Peptide Deletion Leads to Progressive Hypertension, Associated Organ Damage, and Reduced Survival

Abstract

Altered myocardial structure and function, secondary to chronically elevated blood pressure, are leading causes of heart failure and death. B-type natriuretic peptide, a guanylyl cyclase A agonist, is a cardiac hormone integral to cardiovascular regulation. Studies have demonstrated a causal relationship between reduced production and/or impaired B-type natriuretic peptide release, and the development of human hypertension. However, the consequences of B-type natriuretic peptide insufficiency on blood pressure and hypertension-associated complications remain poorly understood. Therefore, the goal of the current study was to create and characterize a novel model of B-type natriuretic peptide deficiency to investigate the effects of B-type natriuretic peptide absence on cardiac and renal structure, function, and survival. Genetic B-type natriuretic peptide deletion was generated in Dahl Salt Sensitive rats. Compared to age-matched controls, B-type natriuretic peptide-knockout rats demonstrated adult-onset hypertension. Increased left ventricular mass with hypertrophy and substantially augmented hypertrophy signaling pathway genes, developed in young adult knock-out rats, which preceded hypertension. Prolonged hypertension led to increased cardiac stiffness, cardiac fibrosis, and thrombi formation. Significant elongation of the QT interval was detected at nine months in knock out rats. Progressive nephropathy was also noted with proteinuria, fibrosis, and glomerular alterations in B-type natriuretic peptide knock out rats. End organ damage contributed to a significant decline in overall survival. Systemic B-type natriuretic peptide over-expression reversed the phenotype of genetic B-type natriuretic peptide deletion. Our results demonstrate the critical role of B-type natriuretic peptide defect in the development of systemic hypertension and associated end organ damage in adulthood.

Novel Histone Deacetylase Inhibitor Modulates Cardiac Peroxisome Proliferator-Activated Receptors and Inflammatory Cytokines in Heart Failure

“…QT interval on the ECG is a measure of the total duration of ventricular activation and recovery, and it corresponds to the duration of the ventricular action potential [24] . In this study, similar to the previous reports, HF rats had significantly prolonged QT interval [25,26] . Although HDAC inhibitors have been shown to prolong the QT interval [27] , we did not detect a prolonged QT interval in the HF rats treated with 50 mg/kg of MPT0E014.…”

Polycystin 2-dependent cardio-protective mechanisms revealed by cardiac stress

“…Studies on BNP knock-out rats have shown a critical role of BNP on blood pressure control and the regulation of cardiac hypertrophy pathways, with young adult BNP knock-out rats developing left ventricular cardiac hypertrophy that precedes hypertension. Moreover, the knock-out rats showed progressive nephropathy [15]. In addition to the natriuretic peptide system that we show here to be disrupted in stressed Pkd2 +/− mice, it will be important to monitor other systems that are markedly disturbed in stress conditions, such as the catecholaminergic and RAAS systems.…”

Bilateral sympathetic stellate ganglionectomy attenuates myocardial remodelling and fibrosis in a rat model of chronic volume overload

“…The cardiomyocyte cross‐sectional area of RV was significantly smaller in AD group than those in AV group ( P < 0.05) (Figure A). Meanwhile, myocardial mRNA expressions of ANP and BNP, known as myocardial hypertrophy markers, were significantly up‐regulated in RV of AV group ( P < 0.01 vs S), mRNA expression of ANP in RV was significantly down‐regulated in AD group compared to AV group, while ANP and BNP expressions were similar among groups in LV (Figure B). We also observed the perivascular coronary fibrosis and found that the perivascular fibrosis ratio was similar among groups ().…”