Therapeutic Delivery of Ang(1-7) via Genetically Modified Probiotic: A Dosing Study

摘要

In recent years a number of beneficial health effects have been ascribed to the renin-angiotensin system (RAS) that extend beyond lowering blood pressure, primarily mediated via the angiotensin-converting enzyme-2 (ACE2)/angiotensin (1-7) or Ang(1-7)/MAS receptor axis. Moreover, once thought as merely a systemic effector, RAS components exist within tissues. The highest tissue concentrations of ACE2 mRNA are located in the gut making it an important target for altering RAS function. Indeed, genetically engineered recombinant probiotics are promising treatment strategies offering delivery of therapeutic proteins with precision. An Ang(1-7) secreting Lactobacillus paracasei (LP) or LP-A has been described for regulation of diabetes and hypertension; however, we are the first to the best of our knowledge to propose this paradigm as it relates to aging. In this Research Practice manuscript, we provide proof of concept for using this technology in a well-characterized rodent model of aging: the Fisher344 x Brown Norway Rat (F344BN). Our primary findings suggest that LP-A increases circulating levels of Ang(1-7) both acutely and chronically (after 8 or 28 treatment days) when administered 3x or 7x/week over 4 weeks. Our future preclinical studies will explore the impact of this treatment on gut and other age-sensitive distal tissues such as brain and muscle.