Cardiac capsaicin‐sensitive sensory nerves regulate myocardial relaxation via S‐nitrosylation of SERCA: role of peroxynitrite

Abstract

Background and purpose: Sensory neuropathy develops in the presence of cardiovascular risk factors (e.g. diabetes, dyslipidemia), but its pathological consequences in the heart are unclear. We have previously shown that systemic sensory chemodenervation by capsaicin leads to impaired myocardial relaxation and diminished cardiac nitric oxide (NO) content. Here we examined the mechanism of diminished NO formation and if it may lead to a reduction of peroxynitrite (ONOO À )-induced S-nitrosylation of sarcoendoplasmic reticulum Ca 2 þ -ATPase (SERCA2a). Experimental approach: Male Wistar rats were treated with capsaicin for 3 days to induce sensory chemodenervation. Seven days later, myocardial function and biochemical parameters were measured. Key results: Capsaicin pretreatment significantly increased left ventricular end-diastolic pressure (LVEDP) decreased cardiac NO level, Ca 2 þ -dependent NO synthase (NOS) activity, and NOS-3 mRNA. Myocardial superoxide content, xanthine oxidoreductase and NADPH oxidase activities did not change, although superoxide dismutase (SOD) activity increased. Myocardial and serum ONOO À concentration and S-nitrosylation of SERCA2a were significantly decreased. Conclusions and implications: Our results show that sensory chemodenervation decreases cardiac NO via decreased expression and activity of Ca 2 þ -dependent NOS and increases SOD activity, thereby leading to decreased basal ONOO À formation and reduction of S-nitrosylation of SERCA2a, which causes impaired myocardial relaxation characterized by increased left ventricular end-diastolic pressure (LVEDP). This suggests that capsaicin sensitive sensory neurons regulate myocardial relaxation via maintaining basal ONOO À formation and SERCA S-nitrosylation.

Serum lipids and cardiac function correlate with nitrotyrosine and MMP activity in coronary artery disease patients

“…A plausible explanation is that while MMP-9 is an abundant enzyme in different cells and tissues including macrophages and leukocytes, MMP-2 is an intracellular enzyme mainly in contractile tissues that can be activated and released e.g. due to acute myocardial ischemia/reperfusion and infarction [8,[21][22][23][24], however, our CAD patient population did not have severe ischemia at the time of tissue sampling, therefore, MMP-2 activation and release can be less sensitively detected in the serum.…”

“…The main effector of nitro-oxidative stress is peroxynitrite, which may activate several enzymes including MMPs via S-nitrosylation/S-glutathiolation of their tyrosine and/or cystein residues [7,8]. Furthermore, peroxynitrite nitrates free tyrosine residues to form nitrotyrosine, which is a widely used marker for peroxynitrite generation [9].…”

Abnormal Ca2+Cycling in Failing Ventricular Myocytes: Role of NOS1-Mediated Nitroso-Redox Balance

“…Unlike RyR, studies have not investigated if NOS1 is able to directly modulate SERCA activity. However, a study demonstrated that SERCA is S-nitrosylated (14), but the NO source responsible for this post-translational modification was not investigated. It has also been reported that nitroxyl (the 1 electron reduction product of NO) is able to modify SERCA via S-glutathiolation of cysteine674 (102).…”

Cytoprotective approaches to protect myocardium against ischemia/reperfusion injury

“…51,[53][54][55][56][57]. However, excess of NO in the presence of the co-existing free radicals have detrimental effect on cell survival.…”