Abnormal Cardiac Autonomic Regulation in Mice Lacking ASIC3

Abstract

Integration of sympathetic and parasympathetic outflow is essential in maintaining normal cardiac autonomic function. Recent studies demonstrate that acid-sensing ion channel 3 (ASIC3) is a sensitive acid sensor for cardiac ischemia and prolonged mild acidification can open ASIC3 and evoke a sustained inward current that fires action potentials in cardiac sensory neurons. However, the physiological role of ASIC3 in cardiac autonomic regulation is not known. In this study, we elucidate the role of ASIC3 in cardiac autonomic function using Asic3 −/− mice. Asic3 −/− mice showed normal baseline heart rate and lower blood pressure as compared with their wild-type littermates. Heart rate variability analyses revealed imbalanced autonomic regulation, with decreased sympathetic function. Furthermore, Asic3 −/− mice demonstrated a blunted response to isoproterenol-induced cardiac tachycardia and prolonged duration to recover to baseline heart rate. Moreover, quantitative RT-PCR analysis of gene expression in sensory ganglia and heart revealed that no gene compensation for muscarinic acetylcholines receptors and beta-adrenalin receptors were found in Asic3 −/− mice. In summary, we unraveled an important role of ASIC3 in regulating cardiac autonomic function, whereby loss of ASIC3 alters the normal physiological response to ischemic stimuli, which reveals new implications for therapy in autonomic nervous system-related cardiovascular diseases.

ASIC3 knockout alters expression and activity of P2X3 in muscle afferent nerves of rat model of peripheral artery disease

“…Baseline BP in WT rats and KO rats: Regarding cardiovascular responses to activation of muscle afferents’ P2X3, it is interesting to observe a decreased baseline of BP and HR in ASIC3 KO rats. This is partly consistent with the previous study from Cheng et al, 34 in which the ASIC3 −/− mice demonstrated a blunt BP response under stress condition and the ratio of the low frequency power spectral density was lower in ASIC3 −/− mice than the ASIC3 +/+ mice. This indicates a blunted effect on the sympathetic control of cardiovascular activity following the global abolishing of the ASIC3.…”

Acid-sensing ion channel 3: An analgesic target

“…Moreover, there is evidence that ASIC3 is also involved in control of blood pressure, as well as regulating breathing rate. For example, ASIC3 −/- mice have a lower systolic and diastolic blood pressure, coupled with a slightly, but not statistically significant, higher heart rate, as a potential compensatory role, compared to WT mice [ 104 ]. The link between ASIC3 and blood pressure regulation is further supported by the human genetic polymorphism rs2288646-A found in Taiwanese individuals, which is associated with a higher frequency of higher systolic and diastolic blood pressure, allele frequency being 9.7% amongst those with hypertension [ 105 ]; however, the effect of this polymorphism on channel function or expression is yet to be determined.…”

Acid-sensing ion channels in sensory signaling

“…In support of this notion, Cheng et al (24) showed that ASIC3-null mice present normal baseline heart rate under basal conditions but abnormal autonomic regulation of cardiac activity in response to isoproterenol-induced myocardial ischemia. In addition, ASIC3-null mice have significative lower systolic and diastolic arterial blood pressure under stress than wild-type littermates (24). In support of the notion that ASIC3 plays a protective role in cardiac ischemia, histological studies revealed that Asic3 KO mice exhibit more severe left ventricular fibrosis and monocyte infiltration 7 days after isoproterenol-induced myocardial ischemia than wildtype littermates (23).…”

“…Activation of cardiac sensory neurons triggers sympathetic activation during cardiovascular disease states (90,97), which was proposed to elicit multifarious cardioprotective signals to limit the severity of the injury (11). In support of this notion, Cheng et al (24) showed that ASIC3-null mice present normal baseline heart rate under basal conditions but abnormal autonomic regulation of cardiac activity in response to isoproterenol-induced myocardial ischemia. In addition, ASIC3-null mice have significative lower systolic and diastolic arterial blood pressure under stress than wild-type littermates (24).…”