NPRC deletion attenuates cardiac fibrosis in diabetic mice by activating PKA/PKG and inhibiting TGF-β1/Smad pathways

Abstract

Cardiac fibrosis plays a key role in the progression of diabetic cardiomyopathy (DCM). Previous studies demonstrated the cardioprotective effects of natriuretic peptides. However, the effects of natriuretic peptide receptor C (NPRC) on cardiac fibrosis in DCM remains unknown. Here, we observed that myocardial NPRC expression was increased in mice and patients with DCM. NPRC −/− diabetic mice showed alleviated cardiac fibrosis, as well as improved cardiac function and remodeling. NPRC knockdown in both cardiac fibroblasts and cardiomyocytes decreased collagen synthesis and proliferation of cardiac fibroblasts. RNA sequencing identified that NPRC deletion up-regulated the expression of TGF-β–induced factor homeobox 1 (TGIF1), which inhibited the phosphorylation of Smad2/3. Furthermore, TGIF1 up-regulation was mediated by the activation of cAMP/PKA and cGMP/PKG signaling induced by NPRC deletion. These findings suggest that NPRC deletion attenuated cardiac fibrosis and improved cardiac remodeling and function in diabetic mice, providing a promising approach to the treatment of diabetic cardiac fibrosis.

The mechanisms and therapeutic potential of clopidogrel in mitigating diabetic cardiomyopathy in db/db mice

“…Substantial evidence suggests that inhibiting the TGF-β1/Smad3 pathway can mitigate myocardial fibrosis in diabetic mice. 34 , 35 Consistent with these findings, we found that Clo alleviated cardiac fibrosis in DCM by inhibiting the TGF-β1/Smad3 signaling pathway. Additionally, the ERK, JNK, and p38 signaling pathways were activated in the cardiac tissue of diabetic mice, and Clo treatment suppressed the phosphorylation of ERK and JNK.…”

Combination of ADAM17 knockdown with eplerenone is more effective than single therapy in ameliorating diabetic cardiomyopathy

“…After 1 week of adaptive feeding, the mice were randomly divided into two groups: a control group and a diabetes mellitus (DM) group. The mice in the DM group were injected intraperitoneally with STZ (MCE, USA) at a dosage of 55 mg/kg daily for five consecutive days, whereas the mice in the control group were injected with citrate buffer alone (Meng et al, 2023). Blood glucose levels were measured using an Accu-Check Active Glucometer (Roche, Shanghai, China).…”

“…Primary cardiac fibroblasts were extracted (Meng et al, 2023) and cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum at 37 °C under 5% CO2. To examine the effect of different concentrations of glucose on ADAM17 expression in cardiac fibroblasts, cardiac fibroblasts at 60% confluence were randomly divided into 6 groups, which were exposed to different treatments in the first part of the in vitro experiments (Figure 6A): (1) 5.5 mM glucose (low-glucose control, LG); (2) a combination of 5.5 mM glucose and 54.5 mM mannitol (high-osmotic-pressure control, HO); (3) 15 mM glucose; (4) 30 mM glucose; (5) 45 mM glucose; (6) 60 mM glucose.…”

Research Progress on Transient Receptor Potential Channels and Myocardial Fibrosis

“…TGF-β1 is the most critical cytokine in the process of myocardial fibrosis [8] . TGF-β1 binds to TGFβRII and TGFβRI, thereby activating activin receptor-like kinase 5 (ALK5), recruiting and phosphorylating its downstream signaling proteins Smad2 and Smad3, and then translocating into the nucleus to induce gene transcription [9] . In addition, TGF-βI can also activate the MAPK non-classical signaling pathway and regulate cell metabolism [10] .…”