HFpEF, a Disease of the Vasculature: A Closer Look at the Other Half Melissa A. Lyle, MD, Frank V. Brozovich, MD, PhD  Mayo Clinic Proceedings  Volume 93, Issue 9, Pages 1305-1314 (September 2018) DOI: 10.1016/j.mayocp.2018.05.001 Copyright © 2018 Mayo Foundation for Medical Education and Research Terms and Conditions

Figure 1 Protein kinase A signaling in cardiac muscle. Activation of the β1-adrenergic receptor activates adenylate cyclase via G protein–coupled receptors and results in an increase in cAMP, which activates PKA. The PKA-mediated phosphorylation (P) of PLB and TN increases lusitropy, whereas the phosphorylation of the L-type Ca2+ channel increases intracelluar Ca2+, which binds to TN to activate the thin filament to increase cardiac contractility (refer to text and reference 18 for details). In addition, PKA signaling mediates cardiac hypertrophy by increasing transcription as well as by increasing Ca2+ and subsequently activating calcineurin (refer to text and reference 19 for details). Both natriuretic peptides and NO activate guanylate cyclase, which results in an increase in cGMP and the activation of PKG. Protein kinase G has been suggested to counteract PKA-mediated cardiac hypertrophy (refer to text and references 20 and 21 for details). ATP = adenosine triphosphate; cAMP = cyclic adenosine 3′,5′-monophosphate; cGMP = cyclic guanosine monophosphate; GMP = guanosine monophosphate; Gs = alpha subunit of G protein; GTP = guanosine 5′-triphosphate; NO = nitric oxide; P = phosphorylation of protein; PDE = phosphodiesterase; PKA = protein kinase A; PKG = protein kinase G; PLB = phospholamban; RyR = ryanodine receptor; SERCA = sarcoplasmic reticulum calcium ATPase; SR = sarcoplasmic reticulum; Tm = tropomyosin; TN = troponin. Mayo Clinic Proceedings 2018 93, 1305-1314DOI: (10.1016/j.mayocp.2018.05.001) Copyright © 2018 Mayo Foundation for Medical Education and Research Terms and Conditions

Figure 2 Regulation of vascular tone. In vascular smooth muscle, activation of G protein–coupled receptors and Gq/11 will lead to an increase in IP3 and DAG. Inositol trisphosphate binds to the IP3 receptor and results in Ca2+ release from the SR, which binds to calmodulin. The Ca2+-calmodulin complex activates MLCK to produce vasoconstriction. Diacylglycerol activates CPI-17, which inhibits MLCP to increase vascular tone. G protein signaling via the activation of G12/13 increases RhoA, which activates Rho kinase. Rho kinase phosphorylates (P) MYPT1 to inhibit MLCP activity to increase vascular tone. In contrast, ACh activates muscarinic receptors on endothelial cells, which results in an activation of NO synthase to produce NO, which in turn activates guanylate synthase and results in an increase in cGMP. Similarly, natriuretic peptides bind to their receptor, which activates guanylate cyclase. The increase in cGMP activates PKG, which decreases intracellular Ca2+ by phosphorylating the K+ channel, Ca2+ channel, and IP3 receptor. Protein kinase G also phosphorylates the LZ+ MYPT1 subunit of MLCP, which activates MLCP, which in turn produces a Ca2+-independent vasodilatation (refer to text and reference 41). ACh = acetylcholine; CPI-17 = protein phosphatase 1 regulatory subunit 14A; cGMP = cyclic guanosine monophosphate; DAG = diacylglycerol; GMP = guanosine monophosphate; GPCR = G protein coupled receptor; GTP = guanosine 5′-triphosphate; Gq/11 = alpha 11 subunit of G protein; G12/13 = alpha 12/13 subunit of G protein; IP3 = inositol trisphosphate; IP3R = inositol trisphosphate receptor; LZ+/LZ− MYPT1 = leucine zipper positive/leucine zipper negative isoform of the myosin-targeting subunit of myosin light chain phosphatase; MLCK = myosin light chain kinase; MLCP = myosin light chain phosphatase; MYPT1 = myosin-targeting subunit of myosin light chain phosphatase; NM = nonmuscle; NO = nitric oxide; P = phosphorylation of protein; PDE = phosphodiesterase; PKC = protein kinase C; PKG = protein kinase G; SM = smooth muscle; SR = sarcoplasmic reticulum. Mayo Clinic Proceedings 2018 93, 1305-1314DOI: (10.1016/j.mayocp.2018.05.001) Copyright © 2018 Mayo Foundation for Medical Education and Research Terms and Conditions