title: Effects of direct Renin inhibition on myocardial fibrosis and cardiac fibroblast function.
abstract: Myocardial fibrosis, a major pathophysiologic substrate of heart failure with preserved ejection fraction (HFPEF), is modulated by multiple pathways including the renin-angiotensin system. Direct renin inhibition is a promising anti-fibrotic therapy since it attenuates the pro-fibrotic effects of renin in addition to that of other effectors of the renin-angiotensin cascade. Here we show that the oral renin inhibitor aliskiren has direct effects on collagen metabolism in cardiac fibroblasts and prevented myocardial collagen deposition in a non-hypertrophic mouse model of myocardial fibrosis. Adult mice were fed hyperhomocysteinemia-inducing diet to induce myocardial fibrosis and treated concomitantly with either vehicle or aliskiren for 12 weeks. Blood pressure and plasma angiotensin II levels were normal in control and hyperhomocysteinemic mice and reduced to levels lower than observed in the control group in the groups treated with aliskiren. Homocysteine-induced myocardial matrix gene expression and fibrosis were also prevented by aliskiren. In vitro studies using adult rat cardiac fibroblasts also showed that aliskiren attenuated the pro-fibrotic pattern of matrix gene and protein expression induced by D,L, homocysteine. Both in vivo and in vitro studies demonstrated that the Akt pathway was activated by homocysteine, and that treatment with aliskiren attenuated Akt activation. In conclusion, aliskiren as mono-therapy has potent and direct effects on myocardial matrix turnover and beneficial effects on diastolic function.
authors.affiliation: Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhi
authors.affiliation: Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Ivan
authors.initials: I
authors.lastname: Luptak
authors.affiliation: Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Alreja
authors.affiliation: Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Jianru
authors.initials: J
authors.lastname: Shi
authors.affiliation: Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Jian
authors.initials: J
authors.lastname: Guan
authors.affiliation: VA Boston Healthcare System, West Roxbury, Massachusetts, United States of America.
authors.forename: Nicole
authors.initials: N
authors.lastname: Metes-Kosik
authors.affiliation: VA Boston Healthcare System, West Roxbury, Massachusetts, United States of America ; Boston University School of Medicine, Boston, Massachusetts, United States of America ; Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Jacob
authors.initials: J
authors.lastname: Joseph
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000804:Angiotensin II / Q000097:blood; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D003094:Collagen / Q000037:antagonists & inhibitors / Q000378:metabolism; D004032:Diet; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts; D005355:Fibrosis; D005650:Fumarates / Q000494:pharmacology*; D006710:Homocysteine / Q000009:adverse effects; D051379:Mice; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D012083:Renin / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D000804:Angiotensin II; D000959:Antihypertensive Agents; D003094:Collagen; D005650:Fumarates; D006710:Homocysteine; D051057:Proto-Oncogene Proteins c-akt; D012083:Renin; D000092502:Renin Inhibitors; C446481:aliskiren