P73Human cardiac biopsy-derived cells improve angiotensin II-induced heart failure

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Abstract

Purpose

Cardiac fibrosis is a hallmark of left ventricular (LV) dysfunction. We isolated and identified novel cells from human cardiac biopsies: cardiac-derived adherent proliferating cells (CAPs). The aim of our study was to evaluate whether CAPs improve angiotensin II (Ang II)-induced heart failure.

Methods

CAPs were isolated from human cardiac biopsies. Ang II (1.8 mg/kg body weight/day) or saline were continuously delivered in C57BL/6 mice by a subcutaneously implanted osmotic pump. One week after the Ang II infusion, 2 x 105 CAPs or PBS were intramyocardially injected. Two weeks after CAPs or PBS application, LV function was determined with a conductance catheter and LVs were harvested for immunohistology, DNA, and RNA isolation. LV interleukin-10 (IL-10) mRNA expression and human Alu presence were quantified via real-time PCR. In vitro, (un)- or L-NAME-treated CAPs were added to un-, Dil- or CFSE-labeled cardiac fibroblasts in the presence or absence of 1 μM Ang II for 24 hours, with or without anti-human IL-10 neutralizing antibody. Reactive oxygen species (ROS), AT1R and alpha-smooth muscle actin (SMA) expression, and fibroblast proliferation were determined by FACS. Collagen production was analyzed via Sirius red staining and anti-collagen I and III immunohistology.

Results

CAPs presence in the murine myocardium was confirmed by human Alu detection. CAPs improved the impaired LV systolic and diastolic function in Ang II-treated mice as indicated by a 1.3-fold (p < 0.01) and 1.4-fold (p < 0.005) increase in LV pressure and dP/dt max, respectively, and a 2.5-fold (p < 0.05) and 1.3-fold (p < 0.05) decrease in LV end diastolic relaxation and dP/dt min, respectively, compared to Ang II-treated mice. In parallel, CAPs normalized the 1.8-fold (p < 0.001) Ang II-induced accumulation of collagen I to levels in PBS control mice. The 6.7-fold (p < 0.001 vs control) increase in collagen III in Ang II-treated mice was reduced by 2.4-fold (p < 0.01) in Ang II + CAPs mice. LV IL-10 mRNA expression was 4.1–fold (p < 0.05) upregulated in Ang II + CAPs versus Ang II + PBS mice. In vitro, addition of CAPs to cardiac fibroblasts decreased the AT1R expression by 2.3-fold and 2.4-fold under basal and Ang II conditions (p < 0.001), respectively, and decreased the Ang II-induced ROS production, alpha-SMA expression, and fibroblast proliferation by 3.2–fold, 2.1-fold and 1.8-fold, respectively (p < 0.05). Furthermore, CAPs reduced the Ang II-induced collagen production by 1.4–fold (p < 0.05). These anti-fibrotic features of CAPs were NO- and IL-10 dependent.

Conclusion

CAPs are promising tools to improve Ang II-induced heart failure.

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