Tale of two kinases: Protein kinase A and Ca2+/calmodulin-dependent protein kinase II in pre-diabetic cardiomyopathy

Table 1 Characteristics of experimental models of pre-diabetic cardiomyopathy

Animal model	MetS parameters							Cardiovascular dysfunction	Ref.
	BW	BP	BG	IR	TG	HDL-C
Dogs
HFD dogs (80% of calories from fat, 5 wk)	↑	↑	↔	+	ND		ND	↑ Heart rate; ↓ Myocardial oxygen delivery and metabolism; ↓ Cardiac index after exercising. ↑ Aortic pressure	Setty et al[51] and Dincer et al[73]
Rats
Sucrose-fed Wistar rats (68%, 7-10 wk)	↔	ND	↔	+	ND		ND	↓ FS; + Systolic dysfunction	Dutta et al[68]
Sucrose-fed Sprague-Dawley rats (68%, 7-10 wk)	↔	ND	↔	+	ND		ND	↔ Heart hypertrophy; ↓ FS; + Systolic dysfunction	Hintz et al[67], and Hintz and Ren[72]
Sucrose-fed Wistar rats (30%, 17-24 wk)	↔	↑	ND	+	↑		↓	↔/↑ Heart rate; ↓ Ventricular pressure; ↑ Arrhythmia incidence after reperfusion	López-Acosta et al[56], and Carvajal and Baños[60]
Sucrose-fed Sprague-Dawley rats (32%, 10 wk)	↑	ND	↑	+	↑		ND	↔ Heart hypertrophy; ↓ FS and EF; ↑ Septum dimension	Vasanji et al[52]
Sucrose-fed Wistar rats (30%, 24 wk)	↑	↑	↔	ND	↑		↔	↔ Heart hypertrophy; + Systolic dysfunction; ↓ Cardiac cell contraction	Barrera-Lechuga et al[53] and Fernández-Miranda et al[70]
Sucrose-fed Wistar rats (30%, 35 wk)	↑	↔	ND	ND	ND		ND	↔ Heart rate; ↔ Heart hypertrophy; ↓ FS	Paulino et al[65]
Sucrose-fed Wistar rats (30%, 16-18 wk)	↔	↔	↔	+	↑		ND	+ Systolic dysfunction	Balderas-Villalobos et al[69]
Sucrose-fed Wistar rats (20%, 8 wk)	↑	ND	↔	+	↔		↓	↓ Heart rate; ↑ SAN rate variability; ↑ SAN fat deposits	Albarado-Ibañez et al[54]
Sucrose-fed Wistar rats (32%, 16 wk)	↑	↑	↑	+	↑		ND	↑ Heart rate; ↑ Heart hypertrophy; ↓ Heart contractility; ↑ Cardiomyocyte lipid deposits; ↑ Aortic pressure	Okatan et al[27,28]
Fructose-fed Wistar rats (10%, 3 wk)	↔	↔	↔	+	↑		↓	↓ Heart rate; ↑ Heart hypertrophy; ↓ FS; ↓ Heart contractility; + Systolic dysfunction; + Diastolic dysfunction; + LV hypertrophy; ↑ Arrhythmia incidence	Sommese et al[55]
HFD Long-Evans rats treated with STZ (40% lard, 21 wk)	↑	↔	↑	+	↔		↔	↔ Heart rate; ↔ Heart hypertrophy; ↔ FS; ↑ Lipid in the myocardium; + Diastolic dysfunction	Koncsos et al[62]
Sucrose-fed Wistar rats (30%, 4 mo)	↑	ND	↔	+	↑		↓	↑ Heart rate; ↔ Heart hypertrophy; + Diastolic dysfunction; ↑ Arrhythmia incidence	Romero-García et al[48] and Landa-Galvan et al[57]
Mice
Fructose-fed C57bl/6 mice (10%, 3 wk)	↔	↔	↔	+	ND	ND		↓ FS; + LV hypertrophy; + Systolic dysfunction	Federico et al[71]
HFD C57bl/6 mice (60% of calories from fat, 8 wk)	↑	ND	↑	ND	↔	ND		↑ Heart rate; ↔ FS; ↑ Arrhythmia incidence	Sánchez et al[63]
HFD FVB-mice (45% of calories from fat, 5 mo)	↑	↔	ND	+	ND	ND		↔ Heart rate; ↑ Heart hypertrophy; ↓ FS; + Systolic dysfunction	Dong et al[66]

↔: No change; +: Presence; ↓: Decreased; ↑: Increased; BG: Blood glucose; BP: Blood pressure; BW: Body weight; EF: Ejection fraction; FS: Fractional shortening; HDL-C: High-density lipoprotein cholesterol; HFD: High-fat diet; IR: Insulin resistance; LV: Left ventricle; MetS: Metabolic syndrome; SAN: Sinus Atrial Node; STZ: Streptozotocin; TG: Triglycerides; ND: Not determined.

Table 2 Alterations in protein kinase A in experimental models of pre-diabetes induced by diet

Experimental model	Kinase modification	Functional effects	Ref.
HFD dogs (80% of calories from fat, 5 wk)	ND	↑ RyR2- Ser2809 phosphorylation	Dincer et al[73]
Sucrose-fed Sprague-Dawley rats (32%, 10 wk)	↑ PKA activity (kemptide phosphorylation)	↓ PLN-Ser16 phosphorylation	Vasanji et al[52]
Sucrose-fed Wistar rats (30%, 35 wk)	↔ expression and activity	↔ PLN-Ser16 phosphorylation; ↓ RyR2- Ser2808 phosphorylation	Paulino et al[65]
Sucrose-fed Wistar rats (32%, 16 wk)	↑ PKA activity (Thr198 phosphorylation)	↑ RyR2- Ser2808 phosphorylation; ↓ PLN-Ser16 phosphorylation	Okatan et al[28]
Fructose-fed Wistar rats(10%, 3 wk)	ND	↔ RyR2- Ser2808 phosphorylation	Sommese et al[55]
HFD Long-Evans rats treated with STZ (40% lard, 21 wk)	ND	↔ PLN-Ser16 phosphorylation	Koncsos et al[62]
HFD C57bl/6 mice (60% of calories from fat, 8 wk)	ND	↔ RyR2- Ser2808 phosphorylation; ↔ PLN-Ser16 phosphorylation	Sánchez et al[63]
Sucrose-fed Wistar rats (30%, 24 wk)	ND	↔ RyR2- Ser2808 phosphorylation; ↔ PLN-Ser16 phosphorylation	Fernández-Miranda et al[70]
Sucrose-fed Wistar rats (30%, 4 mo)	ND	↔ RyR2- Ser2808 phosphorylation; ↔ PLN-Ser16 phosphorylation	Romero-García et al[48]
HFD C57bl/6N mice (45% of total calories from fat, 8 wk)	ND	↔ PLN-Ser16 phosphorylation	Llano-Diez et al[79]

↔: No change; ↓: Decreased; ↑: Increased; ND: Not determined; HFD: High-fat diet; PKA: Protein kinase A; PLN: Phospholamban; RyR2: Ryanodine receptor type 2; STZ: Streptozotocin.

Table 3 Alterations in Ca²⁺/calmodulin-dependent protein kinase II in experimental models of pre-diabetes induced by diet

Experimental model	CaMKII alterations	Functional effects	Ref.
Sucrose-fed Sprague-Dawley rats (32% 10 wk)	↑ CaMKII activity (autocamtide phosphorylation)	↓ PLN-Thr17 phosphorylation	Vasanji et al[52]
Fructose-fed Wistar rats (10%, 3 wk)	↑ CaMKII oxidation; ↔ CaMKII expression	↑ RyR2-Ser2814 phosphorylation	Sommese et al[55]
Sucrose-fed Wistar rats (30%, 4 mo)	↑ CaMKII-Thr287 phosphorylation; ↔ CaMKII expression	↑ RyR2-Ser2814 phosphorylation	Romero-García et al[48]
HFD Long-Evans rats treated with STZ (40% lard, 21 wk)	↔ CaMKII-Thr287 phosphorylation; ↔ CaMKII expression	↔ PLN-Thr17 phosphorylation	Koncsos et al[62]

↔: No change; ↓: Decreased; ↑: Increased; CaMKII: Ca²⁺/calmodulin-dependent protein kinase II; HFD: High-fat diet; PLN: Phospholamban; RyR2: Ryanodine receptor type 2; STZ: Streptozotocin.