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Inhibition of the Renin–Angiotensin System Improves Hemodynamic Function of the Diabetic Rat Heart by Restoring Intracellular Calcium Regulation

Affiliation
Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary;(K.A.P.);(T.I.);(G.A.D.);(Á.F.);(K.T.);(Z.B.)
Paulik, Krisztina Anna;
Affiliation
Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary;(K.A.P.);(T.I.);(G.A.D.);(Á.F.);(K.T.);(Z.B.)
Ivanics, Tamás;
Affiliation
Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary;(K.A.P.);(T.I.);(G.A.D.);(Á.F.);(K.T.);(Z.B.)
Dunay, Gábor A.;
Affiliation
Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary;(K.A.P.);(T.I.);(G.A.D.);(Á.F.);(K.T.);(Z.B.)
Fülöp, Ágnes;
Affiliation
Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary;(K.A.P.);(T.I.);(G.A.D.);(Á.F.);(K.T.);(Z.B.)
Kerék, Margit;
Affiliation
Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary;(K.A.P.);(T.I.);(G.A.D.);(Á.F.);(K.T.);(Z.B.)
Takács, Klára;
Affiliation
Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary;(K.A.P.);(T.I.);(G.A.D.);(Á.F.);(K.T.);(Z.B.)
Benyó, Zoltán;
ORCID
0000-0001-8577-4475
Affiliation
Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary;(K.A.P.);(T.I.);(G.A.D.);(Á.F.);(K.T.);(Z.B.)
Miklós, Zsuzsanna

Background/Objectives: Disrupted intracellular calcium (Ca 2+ i ) regulation and renin–angiotensin system (RAS) activation are pathogenetic factors in diabetic cardiomyopathy, a major complication of type 1 (T1D) and type 2 (T2D) diabetes. This study explored their potential link in diabetic rat hearts. Methods: Experiments were conducted on T1D and T2D Sprague-Dawley rats induced by streptozotocin and fructose-rich diet, respectively. In T1D, rats were treated with Enalapril (Ena) or Losartan (Los) for six weeks, whereas T2D animals received high-dose (HD) or low-dose (LD) Ena for 8 weeks. Heart function was assessed via echocardiography, Ca 2+ i transients by Indo-1 fluorometry in Langendorff-perfused hearts, and key Ca 2+ i cycling proteins by Western blot. Data: mean ± SD. Results: Diabetic hearts exhibited reduced contractile performance that was improved by RAS inhibition both in vivo (ejection fraction (%): T1D model: Control: 79 ± 7, T1D: 54 ± 11, T1D + Ena: 65 ± 10, T1D + Los: 69 ± 10, n = 18, 18, 15, 10; T2D model: Control: 73 ± 8, T2D: 52 ± 6, T2D + LDEna: 62 ± 8, T2D + HDEna: 76 ± 8, n = 9, 8, 6, 7) and ex vivo (+dPressure/dt max (mmHg/s): T1D model: Control: 2532 ± 341, T1D: 2192 ± 208, T1D + Ena: 2523 ± 485, T1D + Los: 2643 ± 455; T2D model: Control: 2514 ± 197, T2D: 1930 ± 291, T2D + LDEna: 2311 ± 289, T2D + HDEna: 2614 ± 268). Analysis of Ca 2+ i transients showed impaired Ca 2+ i release and removal dynamics and increased diastolic Ca 2+ i levels in both models that were restored by Ena and Los treatments. We observed a decrease in sarcoendoplasmic reticulum Ca 2+ -ATPase2a (SERCA2a) expression, accompanied by a compensatory increase in 16Ser-phosphorylated phospholamban (P-PLB) in T2D that was prevented by both LD and HD Ena (expression level (% of Control): SERCA2a: T2D: 36 ± 32, T2D + LDEna: 112 ± 32, T2D + HDEna: 106 ± 30; P-PLB: T2D: 557 ± 156, T2D + LDEna: 129 ± 38, T2D + HDEna: 108 ± 42; n = 4, 4, 4). Conclusions: The study highlights the critical role of RAS activation, most likely occurring at the tissue level, in disrupting Ca 2+ i homeostasis in diabetic cardiomyopathy. RAS inhibition with Ena or Los mitigates these disturbances independent of blood pressure effects, underlining their importance in managing diabetic heart failure.

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Editor:
Fazio, Serafino
Published in:
Biomedicines  
Vol. 13, No. 3 (20.03.2025)
Volume:
13
No.:
3
Date Issued:
20.03.2025
DOI:
10.3390/biomedicines13030757
Language:
English
Type of Resource:
Text
Keywords:
renin–angiotensin system (RAS); losartan; enalapril; Langendorff heart; diabetic cardiomyopathy; type 1 diabetes; type 2 diabetes; cardiac Ca 2+ i transient; Indo-1 surface fluorometry; SERCA2a
DDC:
610 Medizin und Gesundheit

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