Chronic exercise training prevents coronary artery stiffening in aortic-banded miniswine: role of perivascular adipose-derived advanced glycation end products

Abstract

Previous findings from our laboratory have shown increased coronary artery stiffness is associated with increased vascular advanced glycation end product (AGE) levels from aortic‐banded (AB) mini‐swine. Perivascular adipose tissue (PVAT) promotes arterial stiffness, yet the mechanisms underlying PVAT‐related arterial stiffening and whether exercise is therapeutically efficacious in preventing this phenomenon are unknown. We hypothesized that both chronic low‐intensity continuous and interval exercise training (LICT and LIIT, respectively) would prevent PVAT‐related AGE secretion and coronary arterial stiffening in AB mini‐swine. Male Yucatan mini‐swine (8 mo. old) were divided into 4 groups (n=7/group): sedentary control (CON), sedentary AB heart failure (HF), AB plus LICT (HF+LICT), and AB plus LIIT (HF+LIIT). Significance was set at P < 0.05 using one way ANOVA. Following the development of left ventricular (LV) hypertrophy (2 mo. post‐AB), animals began LICT or LIIT consisting of treadmill running 3 days/wk, 55 min/day, for 15 weeks. Only animals in the HF group showed both increased lung weight and LV brain natriuretic peptide mRNA levels, suggestive of heart failure. Coronary artery mechanical stiffness was assessed via a DMT Myograph system, and protein levels in arterial and PVAT samples was examined by immunohistochemistry. HF compared to CON had a significantly lower coronary elastin elastic modulus (EEM) (284.3±27.58 vs. 444.35±37.55 kPa) associated with reduced elastin content. Both LICT and LIIT prevented the decreases in the EEM (474.2±37.83 and 510.6±55.98 kPa, respectively) and coronary elastin content observed in the HF group. Compared to CON, HF animals had significantly increased AGE levels in both the coronary artery and PVAT, along with increased AGE secretion from isolated PVAT samples conditioned in media. Increased PVAT secretion and coronary AGE accumulation were prevented by both LICT and LIIT. To determine if PVAT contributes to arterial stiffness, aortas from young healthy mice exposed to PVAT‐conditioned media were mechanically tested. Aortas exposed to HF‐conditioned media had a significant decrease in the EEM (368.47±20.34 vs. 582.41±28.99 kPa) and decreased elastin content compared to CON, which was prevented when treated with PVAT‐conditioned media from LICT and LIIT animals (542.84±58.09 and 517.8±22.03 kPa, respectively). The AGE inhibitor, aminogunadine (AMG), prevented decreases in the EEM (368.47±20.34 vs. 642.58±35.32 kPa), arterial elastin content, and increases in arterial AGE accumulation observed after exposure to PVAT‐conditioned media from the HF group. In summary, both LICT and LIIT prevent coronary artery stiffness and preserve normal elastin levels via inhibition of PVAT‐derived AGE in a pre‐clinical model of pressure overload‐induced heart failure. Support or Funding Information R01 HL112998 (Emter, PI) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The right ventricular transcriptome signature in Ossabaw swine with cardiometabolic heart failure: implications for the coronary vasculature

“…Briefly, intact, female Ossabaw swine (15-20 kg; 2 mo old) were randomly assigned to either a nonsham sedentary control group (CON; n = 5) that ingested a standard chow diet (5L80, Lab Diet; 3.03 kcal • g À1 , carbohydrate = 71%, protein = 18.5%, and fat = 10.5%; 500 g/day) or a Western dietfed aortic-banded heart failure group (WD-AB; n = 4) that consumed a diet high in fat, high fructose corn syrup, and cholesterol [5B4L, Laboratory Diet; 4.14 kcal g À1 ; carbohydrate, 40.8% (17.8% of total calories from high fructose corn syrup); protein, 16.2%; fat, 43%, 2% cholesterol w/w] (10,(20)(21)(22)(23)(24). At 6 mo of age, an aortic band was placed on the ascending aorta to increase afterload on the heart as previously described (10,(13)(14)(15)(16)(17)(25)(26)(27). A trans-stenotic systolic gradient was set to %70 mmHg (72 ± 2 mmHg) under anesthesia using phenylephrine (iv 1-3 mg/kg/min) to set equivalent hemodynamic conditions defined as a mean aortic pressure (MAP) of %90 mmHg (87 ± 2 mmHg) and a heart rate of %85 beats/min (84 ± 3 bpm).…”

“…IHC was performed by standard procedures as previously described (12,17,42). Segments of RCA were embedded with optimal cutting temperature (OCT) and frozen.…”

“…Right coronary artery stress-strain curves were utilized to calculate the elastin elastic modulus (EEM), an indicator of elastin function and vascular stiffness, as previously described (12,17). The RCA was cleaned of adipose tissue and cut into $1.5-mm segments.…”

“…The RV homogenate assessed herein is composed of a number of cell types including vascular and immune cells, cardiomyocytes, and fibroblasts. Given our laboratory has extensively studied vascular contributions to HF (10)(11)(12)(13)(14)(15)(16)(17), the extension of this study to the coronary vasculature was a logical choice. Our results indicate an increase in JNK1 protein in the RCA that was associated with dysregulation of fibronectin, an extracellular matrix (ECM) component that is a selective target of MAPK8/ JNK1 signaling (18,19).…”

Large Animal Models of Heart Failure

“…Aortic banding was also used to induce chronic pressure overload−induced HF in both 3- and 8-month-old Yucatan miniature swine using a 50- or 70-mm Hg systolic pressure gradient, respectively, placed on the ascending aorta over 6 months (see Figure 1 for surgical visualization) ( 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ). In this model, classic signs of experimental HF included increased LV brain natriuretic peptide mRNA levels and lung weight.…”