Abstract
Both heart failure with reduced (HFrEF) and preserved (HFpEF) ejection fraction are associated with abnormalities of the vasculature, including a resting vasoconstriction and a decrease in sensitivity to nitric oxide (NO) mediated vasodilation. Vascular tone is controlled by the expression and activation of both smooth muscle (SM) and nonmuscle (NM) myosin, and NO mediated vasodilation is regulated by the expression of the leucine zipper positive (LZ+) isoform of the myosin targeting subunit (MYPT1) of myosin light chain phosphatase (MLCP). This study was designed to determine the expression of these contractile proteins in humans with HFrEF and HFpEF vs normal controls. We isolated tertiary mesenteric vessels from remnant biospecimens of patients undergoing partial or total colectomy at Mayo Clinic Rochester from August 2017 to December 2018, and examined the expression of MYPT1 and the LZ + MYPT1 isoform with immunoblots, while 2D SDS-PAGE was used to resolve the phosphorylated and nonphosphorylated regulatory light chains of NM and SM myosin. Our data show that NM myosin expression, as a percentage of total myosin, was 12 ± 3% (controls, n = 6), 7 ± 5% (HFpEF, n = 4) and 37 ± 18% (HFrEF, n = 5, p < 0.05). Total MYPT1 expression was significantly reduced (p < 0.05) in both HFpEF (70 ± 11%) and HFrEF (48 ± 6%); and in HFrEF, LZ + MYPT1 was also depressed (62 ± 19%, <0.05). These results demonstrate that HFrEF and HFpEF are distinct vascular entities, and the changes in protein expression contribute to the vascular abnormalities associated with these diseases. Further in HFpEF, the decrease in MYPT1 would explain why pharmacologic therapies that are designed to activate the NO/cGMP/PKG signaling pathway do not produce a clinical benefit.
Highlights
Heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) have similar clinical presentations, but are clearly two distinct entities
Overall vascular tone is determined by the level of phosphorylation of the smooth muscle myosin regulatory light chain (RLC), which is controlled by the activities of myosin light chain kinase (MLCK) and myosin light chain phosphatase (MLCP) [4]
HFpEF and HFrEF are both associated with a resting vasoconstriction and a decrease in the sensitivity to nitric oxide (NO) mediated vasodilation, which can be produced by alterations in the contractile protein expression and signaling pathways in smooth muscle, or outside the smooth muscle cell, by vessel fibrosis and endothelial dysfunction
Summary
Heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) have similar clinical presentations, but are clearly two distinct entities. An increase in vascular tone can be produced by changes in the expression of contractile proteins within the smooth muscle cell or alterations in the vessel wall, while a decrease in NO sensitivity could be the result of endothelial dysfunction or a decrease in the vascular response to NO. Overall vascular tone is determined by the level of phosphorylation of the smooth muscle myosin regulatory light chain (RLC), which is controlled by the activities of myosin light chain kinase (MLCK) and myosin light chain phosphatase (MLCP) [4]. MLCP is regulated by a number of signaling pathways, which either inhibit MLCP to increase RLC phosphorylation and vascular tone or activate MLCP which decreases RLC phosphorylation and vascular tone [6, 7]. The expression of LZþ/LZ- MYPT1 isoforms is modulated in animal models of sepsis [12], pre-eclampsia [13], pulmonary arterial hypertension [14], and HFrEF [15, 16, 17], which suggests that changes in MYPT1 expression could be important in humans with HFpEF and/or HFrEF
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