Hypertension (HTN) is one of the most prominent risk factors for cardiovascular diseases such as coronary artery disease and congestive heart failure. It is classically associated with hypertensive heart disease (HHD), which has as its hallmarks diastolic dysfunction, cardiac hypertrophy, and myocardial fibrosis. B-type natriuretic peptide (BNP) is a cardiac hormone which controls intravascular volume and arterial pressure to maintain the integrity of circulation. In addition to its diuretic and vasodilatory properties, both of which serve to lower blood pressure, BNP also has direct myocardial tissue effects. Indeed, BNP has anti-fibrotic and anti-hypertrophic properties, which make it a potentially attractive therapeutic for HHD. However, use of BNP for chronic therapy has been limited by its short in vivo half-life. Moreover, due to limited long-term BNP delivery strategies, the influence of continuous BNP treatment on the cardiovascular system and on the heart its self remains elusive. Our recent finding of reduced BNP activation in early stages of human HTN suggests that an impaired BNP system has a role in the development of HTN and its co-morbidities such as HHD. Our central hypothesis is that chronic cardiac BNP over-expression by AAV9-vector-mediated technology in HTN animals ameliorates the development of HHD. The overall goal of this proposal is to advance the biology and therapeutics of BNP, with a specific focus on the influence of vector-mediated chronic cardiac BNP over-expression on cardiac structure and function, especially on the development of HHD.
Our specific aims are i) to evaluate the safety and pharmacokinetics/dynamics of AAV9 vector-mediated cardiac gene transfer, ii) to evaluate novel strategies to self-regulate production and release of BNP in vivo, and iii) to evaluate the therapeutic effects of chronic cardiac BNP delivery in an in vivo model of HHD with diastolic dysfunction and hypertrophy. Accomplishing the specific aims outlined in this proposal will lead to an innovative gene transfer vector strategy that would allow long-term cardiac BNP delivery in the hypertensive heart with diastolic dysfunction and hypertrophy. Our BNP delivery strategy may establish a novel chronic BNP therapy for severe HHD induced by resistant or malignant HTN, ultimately leading to prevention of heart failure.
Cardiovascular disease is the nation's leading cause of death with nearly one million deaths each year. Hypertension is one of the most common risk factors for severe heart disease. Although the heart-derived hormone, B-type natriuretic peptide (BNP), has known anti-hypertrophic, anti-fibrotic, and blood pressure lowering properties that could be very beneficial in hypertensive heart disease (HHD), long-term BNP therapy is limited by its short in vivo half-life. In order to deliver chronic BNP therapy and to evaluate its effects in HHD, we will use a novel vector-mediated technology to deliver the BNP gene to the heart. We will test if regulated long-term cardiac BNP expression ameliorates HHD. Our results will elucidate the role of BNP in hypertension and may lead to a novel chronic BNP therapy strategy for human HHD.
|Ikeda, Y; Makino, A; Matchett, W E et al. (2016) A novel intranuclear RNA vector system for long-term stem cell modification. Gene Ther 23:256-62|
|Holditch, Sara J; Schreiber, Claire A; Burnett, John C et al. (2016) Arterial Remodeling in B-Type Natriuretic Peptide Knock-Out Females. Sci Rep 6:25623|
|Holditch, Sara J; Schreiber, Claire A; Nini, Ryan et al. (2015) B-Type Natriuretic Peptide Deletion Leads to Progressive Hypertension, Associated Organ Damage, and Reduced Survival: Novel Model for Human Hypertension. Hypertension 66:199-210|
|Schreiber, Claire A; Sakuma, Toshie; Izumiya, Yoshihiro et al. (2015) An siRNA Screen Identifies the U2 snRNP Spliceosome as a Host Restriction Factor for Recombinant Adeno-associated Viruses. PLoS Pathog 11:e1005082|
|El Khatib, M M; Sakuma, T; Tonne, J M et al. (2015) Î²-Cell-targeted blockage of PD1 and CTLA4 pathways prevents development of autoimmune diabetes and acute allogeneic islets rejection. Gene Ther 22:430-8|
|Tonne, Jason M; Holditch, Sara J; Oehler, Elise A et al. (2014) Cardiac BNP gene delivery prolongs survival in aged spontaneously hypertensive rats with overt hypertensive heart disease. Aging (Albany NY) 6:311-9|
|Mangiafico, Sarah; Costello-Boerrigter, Lisa C; Andersen, Ingrid A et al. (2013) Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics. Eur Heart J 34:886-893c|
|Cataliotti, Alessandro; Tonne, Jason M; Bellavia, Diego et al. (2011) Long-term cardiac pro-B-type natriuretic peptide gene delivery prevents the development of hypertensive heart disease in spontaneously hypertensive rats. Circulation 123:1297-305|
|Tonne, Jason M; Campbell, Jarryd M; Cataliotti, Alessandro et al. (2011) Secretion of glycosylated pro-B-type natriuretic peptide from normal cardiomyocytes. Clin Chem 57:864-73|