Role of purinergic receptors in the carotid body in heart failure

Abstract

Heart failure is a public health problem and is one of the leading causes of death worldwide. Despite current advances, the prognosis is poor, and there remains no cure for heart failure. Heart failure is characterised by breathlessness (respiratory irregularities), bronchoconstriction, leg oedema, a progressive loss in cardiac output, left ventricular hypertrophy, sleep apnoea, and raised sympathetic activity. This proposal aims to determine a treatment strategy to reduce sympathetic hyperactivity, respiratory irregularities, and bronchoconstriction in heart failure. A clue to a driver of heart failure arises from the strong correlation between peripheral chemoreceptor reflex sensitivity and survival post-myocardial infarction. Of particular interest is the purinergic signalling (ATP and P2X3 receptors), which plays an essential role in both the sensitisation (increase in tonicity) and hyperreflexia of peripheral sensory afferent neurones in several pathological conditions. Activation of carotid body produces release of ATP from type I (glomus) and type II (glial) cells and stimulates purinergic receptors on the terminals of petrosal ganglion afferents, which form a basket like endings on these cells. In the present research project, we will evaluate whether purinergic signalling and glial cells mediate the afferent tonicity and sensitisation within the carotid body in heart failure and explore the potential therapeutic benefit of abolishing aberrant purinergic signalling in a small animal model of heart failure. The following hypotheses will be tested: I) the intrinsic excitability is enhanced and the expression of P2X3 receptors are upregulated in the chemoreceptive petrosal ganglion neurones in rats after myocardial infarction; II) upregulation of P2X3 receptors induces sensitisation of the peripheral chemoreflex responses (respiratory, sympathetic and chemoreceptive neurones) after myocardial infarction; III) ATP bioavailability increased in the carotid body after myocardial infarction, and; IV) following myocardial infarction, chronic genetic manipulation of glomus and glial cells purinergic signalling in the carotid body will lower sympathetic activity, improve cardiac function, reduce respiratory irregularities, bronchoconstriction, left ventricular mass and myocardial fibrosis. We propose that aberrant ATP signalling triggers hypertonicity in the carotid body that via P2X3 receptors plays a crucial role in heart failure progression and offers a therapeutic angle to reverse multiple components (sympathetic hyperactivity, respiratory irregularities, and bronchoconstriction) of its pathogenesis. (AU)