Purpose:
Cardiac fibrosis is linked with hyperglycemia and increases the risk of cardiovascular complications and heart failure. Despite several advancements, the molecular mechanisms responsible for cardiac fibrosis in diabetes remain unclear. The renin-angiotensin system (RAS) is activated and plays an essential role in diabetes-induced cardiac dysfunctions through activation of Ang II. However, angiotensin converting enzyme 2 (ACE2), the protective arm of RAS, opposes the classical RAS functions mediated by ACE. Previously, we have reported that ACE2 deficient exacerbates hyperglycemia-induced gut dysbiosis, increased gut barrier permeability, and facilities translocation of gut microbial peptides (GMPs) into system circulation in type 1 diabetic mice. Here, we sought to determine whether dysbiosis induced by type 2 diabetes and ACE2 deficiency contributes to cardiac fibrosis.
Methods:
Toll-like receptor- (TLR-2) associated inflammatory signaling and cardiac fibrosis were studied in WT, db/db, and ACE2
-/y
-db/db mice with 4-months of diabetes. The levels of peptidoglycan (PGN), a TLR-2 ligand, were measured by ELISA assay. The markers of gut barriers and inflammatory cytokines were assessed by immunohistochemistry and qRT-PCR. To measure cardiac fibrosis, Masson’s trichrome staining was used to stain collagen fibers.
Results:
ACE2
-/y
-db/db mice exhibited increased myocardial fibrosis as compared with db/db and WT mice. In the myocardium, TLR-2 expression (4 folds, p<0.005) and pro-inflammatory cytokines IL-1β (p<0.001), IL-6 (p<0.0001), and TNF-α (p<0.01 were significantly up-regulated in ACE2
-/y
-db/db mice compared with db/db and WT mice. Increased gut barrier permeability as detected by a reduction in expression of tight junction molecules (ZO-1, p120-catenin, and VE-cadherin) and a 2- fold increase in circulating PGN was observed in ACE2
-/y
-db/db mice when compared to db/db.
Conclusions:
These data suggest that PGN and other circulating gut microbial particles may have a deleterious impact on cardiac health by promoting inflammation-mediated fibrosis. In addition to controlling hyperglycemia, strategies aimed at restoring gut barrier integrity may prevent diabetic cardiovascular complications.
Resveratrol Combined with Pioglitazone Ameliorates Cardiovascular Complications in db/db Diabetic Mice
