Letter to the Editor: Ca2+/calmodulin-dependent protein kinase II in heart failure and the role of sodium-glucose-cotransporter 2 inhibitors

Abstract

We read with great interest the meta-analysis by Parsi et al showing the strong therapeutic effects of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in heart failure. Because the expression of sodium-glucose cotransporter-2 in cardiomyocytes is minimal, the exact pathways for their direct cardioprotective actions are not fully defined. In this correspondence, we summarize emerging evidence and advance an integrated view that places Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) as a central molecular target. CaMKII is a key factor in heart failure progression. By phosphorylating a host of key substrates such as ryanodine receptor 2, L-type calcium channels and voltage-gated sodium channel voltage-gated sodium channel type V 1.5, it facilitates ionic imbalance, predisposition to arrhythmia, and structural remodeling. We highlight the way SGLT2i may exercise their benefits through coordinated suppression of CaMKII activity via enhanced ionic homeostasis, decreased oxidative injury and suppressed inflammatory signaling. This mechanistic framework offers a unified explanation for the reported clinical and experimental improvements associated with SGLT2i, such as improved electrical stability, improved systolic and diastolic function, and reduction of pathological cardiac remodeling.

Key Words: Sodium-glucose cotransporter 2 inhibitor; Heart failure; Ca²⁺/calmodulin-dependent protein kinase II; Oxidative stress; Calcium homeostasis

Core Tip: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have revolutionized the treatment of heart failure, but their direct molecular effects in cardiomyocytes, which express little sodium-glucose cotransporter-2, have not been fully described. This letter summarizes current evidence and presents a conceptual framework in which Ca²⁺/calmodulin-dependent protein kinase II is a central target. We hypothesize that many of the cardioprotective effects of SGLT2i are mediated by the dampening of Ca²⁺/calmodulin-dependent protein kinase II activity through synergistic modulation of ionic balance, relief of oxidative stress and inflammatory signaling suppression. Together, these processes may provide a unified explanation for the observed improvements in electrical stability, ventricular performance, and cardiac remodeling associated with SGLT2i treatment.

TO THE EDITOR

We read with great interest the meta-analysis by Parsi et al[1]. This rigorous work offers an excellent and robust synthesis of the randomized evidence, and provides clear evidence that sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) significantly reduce the risks of heart failure (HF) hospitalization, cardiovascular death, and overall mortality. Despite these well-established clinical benefits, the molecular mechanisms underlying these changes are not fully defined, particularly as SGLT2 is minimally expressed in cardiomyocytes. For this reason, the extraordinary cardioprotective effects of SGLT2i remain the subject of scientific study. In correspondence, we summarize emerging findings and offer an integrated perspective: Many of the therapeutic effects of SGLT2i in HF may be largely due to indirect suppression of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), a central regulator of pathological signaling in the failing heart. This proposed mechanism provides a biologically consistent framework that may help to explain the wide range of improvements seen with SGLT2i therapy.

Traditionally, the cardiovascular benefits of SGLT2i have been attributed primarily to systemic effects such as osmotic diuresis and resulting decreases in cardiac preload and afterload. Increasing evidence, however, indicates that these drugs have a variety of direct effects on the myocardium as well. Reported mechanisms include modulation of cardiomyocyte ionic balance, e.g., inhibition of the sodium-hydrogen exchanger 1 and altered activity of the Na⁺/Ca²⁺ exchanger (NCX)[2-4]; changes in cardiac energy metabolism with increased ketone body utilization and improved substrate preference[5,6]; and enhancements in mitochondrial performance, indicated by increased energetic efficiency and reducing oxidative stress[7,8]. While these mechanisms are important, this letter focuses on an additional and increasingly convincing concept: That a large part of the cardioprotective actions of SGLT2i may be mediated by the indirect inhibition of CaMKII, a key regulator of pathological signaling in the failing heart.

THE PIVOTAL ROLE OF CaMKII IN HF

HF is a complex clinical syndrome that is linked to a high degree of morbidity, recurrent hospital admissions and high mortality rates[9]. In recent years, SGLT2i have evolved from being exclusively antihyperglycemic drugs to cornerstone medications for HF with benefits that go far beyond glycemic control[10]. Given that little to no SGLT2 protein is expressed by cardiomyocytes, understanding how these agents provide direct cardiac protection in virtual absence of their canonical target has become an important area of investigation. Accordingly, the current understanding has shifted from consideration of SGLT2i efficacy due mainly to systemic effects, including osmotic diuresis, decreased preload and afterload, and enhanced myocardial energetic efficiency[11], to appreciation of the role of direct, cardiomyocyte-level mechanisms that may be central to the therapeutic effects of these drugs.

The cardiac isoform of CaMKII predominates, and is CaMKIIδ. Under physiological conditions, CaMKIIδ is activated in response to the binding of Ca²⁺/calmodulin to the kinase, which leads to autophosphorylation at Thr287, which changes CaMKIIδ into a persistently active form[12-14]. In disease states, however, CaMKII also can be switched on via calcium-independent pathways. It is interesting to note that reactive oxygen species (ROS) can oxidize Met281/282, leading to a constitutively active oxidized version of the enzyme, an important molecular link between oxidative stress and cardiac dysfunction[15].

DOWNSTREAM PATHOLOGICAL CONSEQUENCES OF ABERRANT CaMKII ACTIVATION

Being a key mediator of HF progression, pathological hyperactivation of CaMKII is a molecular hub that synthesizes a range of upstream perturbations such as ionic dysplasia and oxidative stress and converts them into widespread maladaptive signaling in cardiomyocytes via the phosphorylation of many key downstream targets[16-18]. These CaMKII-induced effects are pro-arrhythmia susceptibility, myocardial fibrotic remodeling and cardiac function deterioration in HF[19,20]. The dysregulated CaMKII signaling has been attributed to the different pathological pathways including electrical instability, structural remodeling, inflammatory activation and programmed cell death.

CaMKII has extensive impacts on electrophysiology and calcium processing in the heart, and in pathological CaMKII activation a number of these systems are impaired. CaMKII-mediated phosphorylation of ryanodine receptor 2 (RyR2) enhances sarcoplasmic reticulum (SR) calcium leak[21-23], whereas CaMKII-mediated phosphorylation of the L-type calcium channel enhances calcium influx and action potential duration[24]. CaMKII also regulates phospholamban that disrupts the activity of sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase 2a and reduces the uptake of SR calcium[25]. These disruptions are also aggravated by CaMKII-mediated up-regulation of NCX[26]. Simultaneously, CaMKII provokes a radical shift in sodium regulation. Its phosphorylation of voltage-gated sodium channel type V 1.5 enhances the late sodium current, which causes intracellular sodium and secondary calcium overload[27,28]. Moreover, CaMKII-modulation of potassium currents, especially the transient outward current, decreases repolarization reserve and disrupts the morphology of the action potential[29,30]. Taken together, all these ionic derangements form a high-risk substrate to arrhythmogenesis and impaired contractile performance (Figure 1 and Table 1)[31].

Figure 1 Downstream pathological mechanisms of aberrant Ca²⁺/calmodulin-dependent protein kinase II activation in heart failure. CaMKII: Ca²⁺/calmodulin-dependent protein kinase II; RyR2: Ryanodine receptor 2; SR: Sarcoplasmic reticulum; PLB: Phospholamban; SERCA2a: Sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase 2a; LTCC: L-type calcium channel; Na_v1.5: Voltage-gated sodium channel type V 1.5; HDAC: Histone deacetylase; ROS: Reactive oxygen species; CaM: Ca²⁺/calmodulin; I_to: Transient outward potassium current; NCX: Na⁺/Ca²⁺ exchanger.

Table 1 Key downstream targets and pathological consequences of aberrant Ca²⁺/calmodulin-dependent protein kinase II activation in heart failure.

Specific target	CaMKII action	Pathophysiological consequence
RyR2	Phosphorylates RyR2 at Ser2814, increasing its open probability	Increased sarcoplasmic reticulum calcium leak, elevated diastolic calcium spark frequency, leading to abnormal calcium transients and triggered arrhythmias
PLB	Phosphorylates PLB at Thr17, relieving its inhibition on SERCA2a	Initially compensatory enhanced calcium reuptake; chronic/over-activation synergizes with SERCA2a downregulation, resulting in reduced SR calcium load and diastolic dysfunction
LTCC	Phosphorylates LTCC at Thr1604, prolonging channel opening and slowing inactivation	Increased calcium influx, prolonged action potential duration, establishing the substrate for early afterdepolarizations; exacerbates calcium overload
Nav1.5	Phosphorylates Nav1.5 at Ser516/Thr594, enhancing the late sodium current	Induces intracellular sodium overload, indirectly worsens calcium overload and action potential prolongation, significantly increasing arrhythmia risk
NCX	Indirectly promotes NCX protein expression via upstream signals (e.g., oxidative stress)	Increases reverse-mode NCX activity, leading to calcium influx and overload, impairing electrophysiological stability
Ito	Reduces Ito current density and function through chronic downregulation and acute phosphorylation-dependent gating modulation	Impairs early repolarization, prolongs action potential duration, and compromises repolarization reserve
HDAC	Phosphorylates and activates class I HDACs (e.g., HDAC1, HDAC3), driving pathological gene reprogramming	Promotes myocardial hypertrophy, fibrosis, and pathological remodeling

CaMKII: Ca²⁺/calmodulin-dependent protein kinase II; RyR2: Ryanodine receptor 2; SR: Sarcoplasmic reticulum; PLB: Phospholamban; SERCA2a: Sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase 2a; LTCC: L-type calcium channel; Na_v1.5: Voltage-gated sodium channel type V 1.5; HDAC: Histone deacetylase; ROS: Reactive oxygen species; CaM: Ca²⁺/calmodulin; I_to: Transient outward potassium current; NCX: Na⁺/Ca²⁺ exchanger.

Beyond its electrophysiological effects, CaMKII is the driver of a plethora of maladaptive structural, transcriptional and inflammatory responses. By phosphorylating class I histone deacetylases, CaMKII causes pathological transcriptional reprogramming leading to cardiomyocyte hypertrophy and fibrotic remodeling and progressive ventricular structural deterioration[32]. Moreover, oxidized CaMKII is a focal mediator of inflammation and cell injury. It triggers the nuclear factor kappa B pathway and upregulates the NACHT, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome, which enhances the pro-inflammatory signaling in the myocardium[33,34]. Programmed cardiomyocyte death is also caused by excessive CaMKII activity. CaMKII overactivation contributes to cellular damage and increased functional impairment of the failing heart through interference with mitochondrial calcium homeostasis, stimulation of mitochondrial permeability transition pore opening, and increased production of ROS[35-37].

In summary, pathological activation of CaMKII orchestrates a range of maladaptive processes, including ionic balance disturbance, mitochondrial dysfunction, programmed cell death, fibrotic remodeling, and arrhythmia susceptibility, which collectively impair electrical stability and lead to decreased overall cardiac performance[18,38].

THE UNIFIED CAMKII MECHANISM UNDERLYING SGLT2I CARDIOPROTECTION

Accumulating evidence has suggested that SGLT2i can directly inhibit the pathological activation and phosphorylation of CaMKII and its key downstream targets. For example, dapagliflozin has been found to decrease CaMKII Thr287 autophosphorylation and total kinase activity in models of overstimulation of the β-adrenergic system, decreasing the phosphorylation of RyR2, restoring Ca²⁺ homeostasis and improving cardiac function[39]. Similarly, empagliflozin inhibits both the autophosphorylation of CaMKII and the phosphorylation of RyR2 Ser2814 in the context of experimental models of diabetic cardiomyopathy, leading to a reduction in SR calcium leak, an increase in calcium storage, a decrease in the susceptibility to arrhythmia and an increase in diastolic function[40].

Importantly, SGLT2i also indirectly suppress CaMKII activity by rectifying the ionic disturbances upstream. Mustroph et al[41] has shown that empagliflozin causes a rapid decrease of intracellular sodium concentration, resulting in long-lasting suppression of CaMKII activity and RyR2 phosphorylation, ultimately leading to improved calcium handling and contractile function. This effect is mediated, to a large extent, by inhibition of overactive sodium-hydrogen exchanger 1[42], by reducing sodium overload at its source. The resulting reduction of reverse-mode NCX activity reduces calcium influx, opposing the resulting accumulation of calcium inside the cell that is responsible for the activation of CaMKII. Notably, CaMKII itself can cause ionic imbalance by phosphorylating voltage-gated sodium channel type V 1.5, increasing the late sodium current, and further accumulating sodium and calcium. Empagliflozin acts on both CaMKII and the late sodium current[43], and acts in a synergistic manner to disrupt this self-perpetuating cycle and stabilize cardiac electrophysiology.

In addition to stabilizing the ionic homeostasis, SGLT2i restrict the excessive activation of CaMKII by modulating the oxidative stress and myocardial metabolism. Empagliflozin, for example, inhibits production of mitochondrial ROS after exposure to doxorubicin, thereby preventing the generation of oxidatively activated CaMKII and the reversal of associated abnormalities of calcium handling and contractile function[30]. Moreover, by improving myocardial metabolic efficiency, empagliflozin reduces ROS production at the source, further blocking CaMKII oxidative activation. Mechanistically, this involves the activation of pathways such as AMP-activated protein kinase, which enhances metabolic flexibility, mitochondrial biogenesis and function and optimizes cellular energy and redox balance, collectively lessening oxidative modification of CaMKII at Met281/282[8,44].

SGLT2i also inhibit CaMKII-induced inflammatory signaling and cell death. Specifically, in HF, pathological CaMKII activation promotes the activation of the NLRP3 inflammasome, thereby triggering cardiomyocyte pyroptosis, exacerbating myocardial inflammation and fibrosis[45,46]. Targeting this inflammatory cascade, empagliflozin has been shown to suppress these pro-inflammatory pathways, reduce NLRP3 inflammasome activation, and improve cardiac function in HF models in a Ca²⁺-dependent manner[47]. Thus, through re-establishing ionic balance and directly inhibiting CaMKII, SGLT2i achieve a synergistic effect on the upstream triggers of myocardial inflammation and cell death, which improves the inflammatory milieu and limits adverse remodeling. This mechanism provides an important explanation for the broad spectrum of cardioprotective effects observed with SGLT2i therapy[48].

In summary, based on current evidence, it is suggested that SGLT2i achieve their widespread cardioprotective effects through the simultaneous modulation of ionic homeostasis, energy metabolism, redox balance and inflammatory signaling converging on the suppression of CaMKII activity[17,48,49]. This integrated view supports the idea that inhibition of CaMKII may be a unifying mechanism for SGLT2i-mediated cardiac protection. While compelling in preclinical models, this hypothesis now needs to be tested directly in humans, using functional studies and causal inference analyses.

CONCLUSION

In conclusion, a CaMKII-centered framework offers a coherent explanation for the various cardioprotective effects of SGLT2i in HF. Confirming this model and determining its causal relevance in patients will require rigorous and well-designed clinical investigations.