Prostaglandin F2(α)-F-prostanoid (PGF2(α)-FP) receptor is closely related to
insulin resistance, which plays a causal role in the pathogenesis of
diabetic cardiomyopathy (DCM). We sought to reveal whether PGF2(α)-FP receptor plays an important part in modulating DCM and the mechanisms involved. We established the
type 2 diabetes rat model by high-fat diet and low-dose
streptozotocin (STZ) and then evaluated its characteristics by metabolite tests, Western blot analysis for
FP-receptor expression, histopathologic analyses of cardiomyocyte density and
fibrosis area. Next, we used gene silencing to investigate the role of
FP receptor in the pathophysiologic features of DCM. Our study showed
elevated cholesterol,
triglyceride,
glucose, and
insulin levels, severe
insulin resistance, and
FP-receptor overexpression in diabetic rats. The
collagen volume fraction (CVF) and perivascular
collagen area/
luminal area (PVCA/LA) were higher in the diabetic group than the control group (CVF% 10.99 ± 0.99 vs 1.59 ± 0.18, P < 0.05; PVCA/LA% 17.07 ± 2.61 vs 2.86 ± 0.69, P < 0.05). We found that the silencing of
FP receptor decreased
cholesterol,
triglyceride,
glucose, and
insulin levels and ameliorated
insulin resistance. The CVF and PVCF/LA were significantly downregulated in
FP-receptor short hairpin RNA (
shRNA) treatment group (
FP-receptor shRNA group vs vehicle group: CVF% 5.59 ± 0.92 vs 10.97 ± 1.33, P < 0.05, PVCA/LA% 4.74 ± 1.57 vs 14.79 ± 2.22, P < 0.05;
FP-receptor shRNA + PGF2(α) group vs vehicle group : CVF% 5.19 ± 0.79 vs 10.97 ± 1.33, P < 0.05, PVCA/LA% 5.96 ± 1.15 vs 14.79 ± 2.22, P < 0.05, respectively). Furthermore, with
FP-receptor gene silencing, the activated
protein kinase C (PKC) and
Rho kinase were significantly decreased, and the blunted phosphorylation of Akt was restored.
FP-receptor gene silencing may exert a protective effect on DCM by improving myocardial
fibrosis, suggesting a new therapeutic approach for human DCM.
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