Cardiac sympathetic innervation and PGP9.5 expression by cardiomyocytes after myocardial infarction: effects of central MR blockade

Abstract

Drobysheva A, Ahmad M, White R, Wang H, Leenen FH. Cardiac sympathetic innervation and PGP9.5 expression by cardiomyocytes after myocardial infarction: effects of central MR blockade. Am J Physiol Heart Circ Physiol 305: H1817-H1829, 2013. First published October 11, 2013; doi:10.1152/ajpheart.00445.2013.-Central mechanisms involving mineralocorticoid receptor (MR) activation contribute to an increase in sympathetic tone after myocardial infarction (MI). We hypothesized that this central mechanism also contributes to cardiac sympathetic axonal sprouting and that central MR blockade reduces cardiac sympathetic hyperinnervation post-MI. Post-MI, tyrosine hydroxylase (TH) and norepinephrine transporter protein content in the noninfarcted base of the heart remained unaltered. In contrast, protein gene product (PGP)9.5 protein was increased twofold in the base of the heart and sixfold in the peri-infarct area at 1 wk post-MI and was associated with increased ubiquitin expression. These changes persisted to a lesser extent at 4 wk post-MI and were no longer present at 12 wk. Cardiac myocytes rather than sympathetic axons were the main source of this elevated PGP9.5 expression. At 7-10 days post-MI, in the peri-infarct area, sympathetic hyperinnervation was observed with a fourfold increase in growth-associated protein 43, a twofold increase in TH, and a 50% increase in PGP9.5-positive fibers compared with the epicardial side of the left ventricle in sham rats. Central infusion of the MR blocker eplerenone markedly attenuated these increases in nerve densities but did not affect overall cardiac PGP9.5 and ubiquitin protein overexpression. We conclude that central MR activation contributes to sympathetic hyperinnervation, possibly by decreasing cardiac sympathetic activity post-MI, or by affecting other mechanisms, such as the expression of nerve growth factor. Marked PGP9.5 expression occurs in cardiomyocytes early post-MI, which may contribute to the increase in ubiquitin. myocardial infarction; cardiac sympathetic hyperinnervation; brain mineralocorticoid receptors; eplerenone; ubiquitin; protein gene product 9.5 CARDIAC REMODELING after myocardial infarction (MI) affects both infarcted and noninfarcted areas of the heart and contributes to the impairment of ventricular performance (19,43,44). Cardiac sympathetic hyperactivity enhances maladaptive cardiac remodeling post-MI and plays a major role in the development of chronic heart failure (CHF) (5, 31). In humans with mild CHF, there is a selective increase in cardiac sympathetic activity, which is followed by augmented sympathetic outflow to skeletal muscle and the kidneys as CHF progresses (16,38). In rats, direct recordings from cardiac sympathetic nerves demonstrate that cardiac sympathetic nerve activity (CSNA) increased twofold within hours after MI (40). In conscious sheep, CSNA was significantly increased by the second hour post-MI and remained elevated for at least 1 wk (14).Increased CSNA may also contribute to the development of cardiac sympathetic hyperi...

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Ubiquitin C-terminal hydrolase L1 (UCHL1) regulates post-myocardial infarction cardiac fibrosis through glucose-regulated protein of 78 kDa (GRP78)

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β-Adrenergic receptor stimulation inhibits proarrhythmic alternans in postinfarction border zone cardiomyocytes: a computational analysis

“…1 A ), which is then translated to repolarization alternans via the Na + /Ca 2+ exchanger and other Ca 2+ -sensitive currents ( 31 ). However, remodeling in the BZ is complex, involving electrophysiological changes ( 42 ), cellular decoupling ( 47 ), and acute sympathetic denervation followed by sympathetic hyperinnervation ( 3 , 12 ). The exact electrophysiological mechanisms determining how MI promotes alternans formation as well as the potential regulatory effects of sympathetic stimulation remain incompletely understood.…”