Regulation of mechanical intercellular junctions and components of the mitochondrial electron transport chain and the TCA cycle in the hypertrophic heart by pyridostigmine or trandolapril

Figures

• 

  FIGURE 1. Gene ontology analysis of enriched biological processes by the DAVID tool. The negative -log10 transformed p-values of enriched biological processes are indicated for comparisons SC/WC (A), SP/SC (B), ST/SC (C), WP/WC (D), WT/WC (E), SP/WP (F) and ST/WT (G).

• 

  FIGURE 2. Alterations in phosphorylation of proteins related to gap and adherens juctions. Proteins with altered phosphorylation in comparisons of control SHR versus WKY rats (SC/WC), pyridostigmine-treated SHR versus control SHR rats (SP/SC), and trandolapril-treated SHR versus control SHR rats (ST/SC) are labeled with gene names and protein identifiers from the UniProt database (www.uniprot.org). Phosphosites are annotated using standard amino acid abbreviations (S, serine; T, threonine; Y, tyrosine) followed by their position within the protein sequence. Small upward and downward arrows indicate increased and decreased phosphorylation, respectively. Pairwise experimental comparisons are distinguished by color (SP/SC, blue; ST/SC, green; concurrent alterations in SP/SC and ST/SC, red; SC/WC, yellow). Protein associations and interactions are indicated by arrows denoting stimulatory or inhibitory effects and are organized according to Palatinus et al. (2012), Sun et al. (2014), Zhao et al. (2019), Rampazzo et al. (2014), Li (2014), Sheikh et al. (2009). Abbreviations: Cdh2, cadherin-2/N-cadherin; Ctnna1, catenin α-1; Ctnna3, catenin α-3; Ctnnb1, catenin β-1; Ctnnd1, catenin δ-1; Dsg2,…

• 

  FIGURE 3. Alterations in phosphorylation of proteins related to desmosomes. The description and layout of the figure are the same as in Figure 2. Protein associations and interactions are organized according to Zhao et al. (2019), Rampazzo et al. (2014), Li (2014), Sheikh et al. (2009), Pernigo et al. (2017), Berika and Garrod (2014), Goldmann (2018), Lange et al. (2020), Kostan et al. (2021), Lin et al. (2021), Mohammed and Chidkey (2021), Su et al. (2022). Abbreviations: Ank2, ankyrin-2; Des, desmin; Dsg2, desmoglein-2; Dsp, desmoplakin; Jup, junction plakoglobin; Lmna, lamin A; Myh6, myosin-6; Myh7, myosin-7; Myl2, myosin regulatory light chain 2; Myom1, myomesin-1; Myom2, myomesin-2; Myot, myotilin; Obscn, obscurin; Pkp2, plakophilin-2; Plec, plectin; Sgca, α-sarcoglykan; Sync, syncoilin; Tnni3, troponin I, cardiac muscle; Tnnt3, troponin T, fast skeletal muscle; Tpm1, tropomyosin-1; Ttn, titin.

• 

  FIGURE 4. Alterations in expression and phosphorylation of proteins related to the mitochondrial electron transport chain. Proteins with altered expression (black) or phosphorylation (red) in comparisons of control SHR versus WKY rats (SC/WC), pyridostigmine-treated SHR versus control SHR rats (SP/SC), and trandolapril-treated SHR versus control SHR rats (ST/SC) are labeled with gene names and UniProt protein identifiers (www.uniprot.org). The description and layout of the figure are identical to those in Figure 2. Protein associations and interactions are indicated by arrows denoting stimulatory or inhibitory effects and are organized according to Hock et al. (2020). Abbreviations: Atp5a1, ATP synthase subunit α; Atp5d, ATP synthase subunit δ; Atp5sl, Distal membrane-arm assembly complex protein 2; Atpaf1, ATP synthase mitochondrial F1 complex assembly factor 1; Cmc1, COX assembly mitochondrial protein; Coa7, Cytochrome c oxidase assembly factor 7; Cox5a, Cytochrome c oxidase subunit 5A; Cox5b, Cytochrome c oxidase subunit 5B; Dhodh, Dihydroorotate dehydrogenase (quinone); Foxred1, FAD-dependent oxidoreductase domain-containing 1; Mtco3, Cytochrome c oxidase subunit 3; Mt-atp6, ATP…

• 

  FIGURE 5. Alterations in expression and phosphorylation of proteins related to mitochondrial metabolic pathways. The description and layout of the figure are identical to those in Figure 4. Protein associations and interactions are organized according to Arnold and Finley (2023) and Houten et al. (2016). Abbreviations: α-KG, α-ketoglutarate; Acaa2, 3-ketoacyl-CoA thiolase; Acaca, Acetyl-CoA carboxylase 1; Acacb, Acetyl CoA carboxylase; Acss2, Propionate—CoA ligase; Cs, Citrate synthase; Hadhb, Trifunctional enzyme subunit β; Mcee, Methylmalonyl CoA epimerase; Mdh2, Malate dehydrogenase 2; Mpc2, Mitochondrial pyruvate carrier 2; Ogdhl, 2-oxoglutarate dehydrogenase-like; Pcca, Propionyl-CoA carboxylase α chain; Pdha/Pdha1l1, Pyruvate dehydrogenase E1 component subunit α; Pdp1, Pyruvate dehydrogenase (acetyl-transferring))-phosphatase 1.

• 

  FIGURE 6. The effect of trandolapril on morphological and molecular changes in intercalated discs during hypertensive left ventricular hypertrophy can be summarized as follows: in the normal heart, intercalated discs—comprising adherens junctions and desmosomes—are thin, symmetric, and highly organized, with components of mechanical junctions predominantly in a phosphorylated state. In contrast, cardiac hypertrophy is characterized by thicker, irregularly shaped intercalated discs and by dephosphorylation of junctional components. The primary effect of trandolapril in hypertensive SHR hearts is the attenuation of hypertrophy and the restoration of the phosphorylation state of mechanical junction proteins.