TRPV4 blockade suppresses atrial fibrillation in sterile pericarditis rats

Abstract

Atrial fibrillation (AF) commonly occurs after surgery and is associated with atrial remodeling. TRPV4 is functionally expressed in the heart, and its activation affects cardiac structure and functions. We hypothesized that TRPV4 blockade alleviates atrial remodeling and reduces AF induction in sterile pericarditis (SP) rats. TRPV4 antagonist GSK2193874 or vehicle was orally administered 1 d before pericardiotomy. AF susceptibility and atrial function were assessed using in vivo electrophysiology, ex vivo optical mapping, patch-clamp, and molecular biology on day 3 after surgery. TRPV4 expression increased in the atria of SP rats and patients with AF. GSK2193874 significantly reduced AF vulnerability in vivo and the frequency of atrial ectopy and AF with a reentrant pattern ex vivo. Mechanistically, GSK2193874 reversed the abnormal action potential duration (APD) prolongation in atrial myocytes through the regulation of voltage-gated K + currents (IK), reduced the activation of atrial fibroblasts by inhibiting P38, AKT, and STAT3 pathways, and alleviated the infiltration of immune cells. Our results reveal that TRPV4 blockade prevents abnormal changes in atrial myocyte electrophysiology and ameliorated atrial fibrosis and inflammation in SP rats, and, therefore, might be a promising strategy to treat AF, particularly post-operative AF.

TRPV4-induced Müller cell gliosis and TNF-α elevation-mediated retinal ganglion cell apoptosis in glaucomatous rats via JAK2/STAT3/NF-κB pathway

“…Previous studies demonstrated that the JAK2–STAT3 pathway is involved in glial activation and cytokine expression [ 58 – 60 ]. Moreover, in the context of neurological inflammatory signaling cascades, TRPV4 reportedly exacerbates neuro-inflammatory actions through the activation of pro-inflammatory STAT3 signaling [ 61 , 62 ]. Furthermore, the inhibition of STAT3 phosphorylation via JAK2 blockade has been shown to reduce hypoxic ischemia-induced neuroinflammation and tissue loss [ 63 ].…”

Interleukin-6-Mediated-Ca2+ Handling Abnormalities Contributes to Atrial Fibrillation in Sterile Pericarditis Rats

“…Postoperative atrial fibrillation (POAF), the most common complication of cardiac surgery, the prevalence of which varies between 20% and 40% in different studies, usually occurs 2-4 days after surgery, causing substantial increases in lengths and costs of hospital stay ( 1 ). Local inflammation, which is related to surgical lesions and postoperative pericarditis, is a major transient factor that may trigger POAF ( 2 – 6 ). Some clinical observations suggest that interleukin (IL)-6, a crucial pro-inflammatory cytokine, is elevated in patients with POAF ( 7 – 9 ).…”

“…Some clinical observations suggest that interleukin (IL)-6, a crucial pro-inflammatory cytokine, is elevated in patients with POAF ( 7 – 9 ). Moreover, IL-6 is early upregulated in the atria of rat and canine sterile pericarditis (SP), which are animal models of POAF ( 2 – 5 ). We found that IL-6 predisposes to atrial fibrosis and fibrillation by inducing cardiac fibroblast activation in SP rats ( 3 , 4 ), which is further confirmed by Liu et al.…”

Calcium and Heart Failure: How Did We Get Here and Where Are We Going?

“…Moreover, the mechanistic link between TRPCs and Ca 2+ mishandling has been reported in multiple experimental models of cardiac disease including myocardial infarction [ 66 , 81 , 82 , 83 , 84 , 85 , 86 , 87 ], atrial fibrillation [ 88 , 89 , 90 , 91 ], and iron overload cardiomyopathy [ 92 ]. In addition to TRPCs, other members of the TRP superfamily [ 93 , 94 , 95 ], e.g., melastatin (TRPM) [ 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 ] and vanilloid (TRPV) subtypes [ 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 ], are also potential candidates mediating the non-canonical Ca 2+ entry into cardiomyocytes.…”