Tonne Jason M, Holditch Sara J, Oehler Elise A, Schreiber Claire A, Ikeda Yasuhiro, Cataliotti Alessandro
Department of Molecular Medicine, Mayo Clinic, College of Medicine, Rochester, MN 55905, USA.
Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Departments of Medicine and Physiology, Mayo Clinic, College of Medicine, Rochester, MN 55905, USA.
Aging (Albany NY). 2014 Apr;6(4):311-9. doi: 10.18632/aging.100655.
Hypertension is a highly prevalent disease associated with cardiovascular morbidity and mortality. Recent studies suggest that patients with hypertension also have a deficiency of certain cardiac peptides. Previously we demonstrated that a single intravenous injection of the myocardium-tropic adeno-associated virus (AAV) 9-based vector encoding for proBNP prevented the development of hypertensive heart disease (HHD) in spontaneously hypertensive rats (SHRs). The current study was designed to determine the duration of cardiac transduction after a single AAV9 injection and to determine whether cardiac BNP overexpression can delay the progression of previously established HHD, and improve survival in aged SHRs with overt HHD.
To evaluate the duration of cardiac transduction induced by the AAV9 vector, we used four week old SHRs. Effective long-term selective cardiac transduction was determined by luciferase expression. A single intravenous administration of a luciferase-expressing AAV9 vector resulted in efficient cardiac gene delivery for up to 18-months. In aged SHRs (9-months of age), echocardiographic studies demonstrated progression of HHD in untreated controls, while AAV9-BNP vector treatment arrested the deterioration of cardiac function at six months post-injection (15-months of age). Aged SHRs with established overt HHD were further monitored to investigate survival. A single intravenous injection of the AAV9-vector encoding rat proBNP was associated with significantly prolonged survival in the treated SHRs (613?38 days, up to 669 days) compared to the untreated rats (480±69 days, up to 545 days)(p<0.05).
A single intravenous injection of AAV9 vector elicited prolonged cardiac transduction (up to 18 months post-injection). AAV9 induced cardiac BNP overexpression prevented development of congestive heart failure, and significantly prolonged the survival of aged SHRs with previously established overt HHD. These findings support the beneficial effects of chronic supplementation of BNP in a frequent and highly morbid condition such as HHD.
高血压是一种与心血管疾病发病率和死亡率相关的高度流行疾病。最近的研究表明，高血压患者还存在某些心脏肽缺乏的情况。此前我们证明，单次静脉注射编码proBNP的心肌靶向腺相关病毒（AAV）9载体可预防自发性高血压大鼠（SHR）发生高血压性心脏病（HHD）。本研究旨在确定单次注射AAV9后心脏转导的持续时间，并确定心脏BNP过表达是否能延缓先前已确立的HHD的进展，以及改善患有明显HHD的老年SHR的生存率。
为评估AAV9载体诱导的心脏转导持续时间，我们使用了4周龄的SHR。通过荧光素酶表达来确定有效的长期选择性心脏转导。单次静脉注射表达荧光素酶的AAV9载体可实现长达18个月的高效心脏基因递送。在老年SHR（9月龄）中，超声心动图研究显示未治疗的对照组中HHD有所进展，而AAV9-BNP载体治疗在注射后6个月（15月龄）时阻止了心脏功能的恶化。对患有已确立明显HHD的老年SHR进行进一步监测以研究生存率。与未治疗的大鼠（480±69天，最长545天）相比，单次静脉注射编码大鼠proBNP的AAV9载体可使治疗的SHR的生存期显著延长（613±38天，最长669天）（p<0.05）。
单次静脉注射AAV9载体可引发长时间的心脏转导（注射后长达18个月）。AAV9诱导的心脏BNP过表达可预防充血性心力衰竭的发生，并显著延长患有先前已确立明显HHD的老年SHR的生存期。这些发现支持了在HHD这种常见且高发病率的疾病中持续补充BNP的有益作用。
