Tirzepatide protects the heart from doxorubicin-induced cardiotoxicity by modulating endoplasmic reticulum (ER) stress and HMGCoA reductase 1 expression

This editorial refers to ‘Tirzepatide alleviates doxorubicin-induced cardiotoxicity via inhibiting HRD1-mediated Nrf2 ubiquitination’ by D. Yang et al., https://doi.org/10.1093/cvr/cvaf033.

Incretin hormones, including glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), glucagon and amylin, are expressed in the intestine.¹ When released from the intestine in response to nutrient intake, they act on cells in the pancreas to decrease glucagon secretion and increase insulin secretion, which contributes significantly to the overall effects of incretins on metabolism, appetite, and body weight. Tirzepatide is a 39 amino acid synthetic peptide that acts as an incretin mimetic, binding to both GLP-1 and GIP1 receptors, which, in addition to pancreas are located in many organs, including the heart. Interest in incretin mimetics was heightened when clinical trials demonstrated that tirzepatide is effective against obesity, Type-2 insulin-dependent diabetes, atherosclerosis, and heart failure. In fact, most of these salutary effects of tirzepatide can be attributed to its abilities to normalize plasma glucose.² Relatedly, tirzepatide has been shown to alleviate the multi-organ ER stress in hyperglycaemia and in so doing decrease maladaptive effects of ER stress.³

Doxorubicin (Dox) is an anthracycline with potent anti-tumour effects. However, it can have major deleterious side effects, including delayed development of heart failure. While such effects impact the utility of Dox, it remains the treatment of choice for treating certain solid tumours, as well as blood dyscrasias such as lymphoma. One maladaptive cardiotoxic effect of Dox on the heart is the induction of oxidative and ER stress.⁴ In this issue of Cardiovascular Research, Yang et al.⁵ examined whether tirzepatide might decrease Dox-induced cardiotoxicity in a pre-clinical mouse model, as well as in cardiac myocytes, in vitro. Indeed, they found that tirzepatide pre-treatment did reduce subsequent Dox-induced cardiotoxicity in mice, and their molecular analyses indicated that it was by reducing oxidative stress that tirzepatide had these remarkable cardioprotective effects. They also showed that these protective effects of tirzepatide were due to its ability to decrease Dox-induced ER stress in the heart, which decreased expression of numerous ER stress-inducible genes, including the trans-ER membrane E3 ubiquitin ligase, HMGCoA reductase 1 (Hrd1) (Figure 1A).

Hrd1 is an essential part of the ER unfolded protein response (UPR), as it participates in ER-associated protein degradation (ERAD), which is responsible for the degradation of terminally misfolded proteins arising upon ER stress.⁶ During ERAD, misfolded ER proteins are translocated out of the ER to the cytosolic face of the ER (Figure 1B; Steps 1 and 2), where they are ubiquitylated by Hrd1 (Step 3), which adaptively targets misfolded ER proteins for proteasome-mediated degradation, thus avoiding proteotoxicity (Step 4). Hrd1 is upregulated by ER stress, presumably so it can remove toxic misfolded proteins. Recently, it has been found that Hrd1 is not restricted to ubiquitylating ER-derived misfolded proteins, but it can ubiquitylate cytosolic proteins that never were in the ER, including the transcription factor Nrf2,⁷ which is well known to induce numerous antioxidant genes, the protein products of which reduce damaging reactive oxygen species. Here, Yang et al.⁵ found that Dox induced ER stress, which increased Hrd1, as expected, but unexpectedly, Hrd1-mediated degradation of Nrf2, which maladaptively exacerbated oxidative stress in response to Dox (Figure 1C and D [left]). Moreover, Yang et al.⁵ found that tirzepatide decreased ER stress, which subsequently decreased Hrd1, thus increasing Nrf2-mediated induction of adaptive anti-oxidative stress gene expression.

While these findings are intriguing, they also lead to additional questions that suggest a more complicated mechanism. The UPR was discovered as an adaptive response to ER stress, a response that induces genes, such as Hrd1, that are well known to protect against toxic protein accumulation in the ER.⁸ It has also been shown that if the UPR is not sufficient to remove toxic misfolded ER proteins, it converts to maladaptive and in many cases leads to apoptotic cell death. It is thought that the conversion from adaptive to maladaptive is at least partly the result of different UPR gene programmes during each phase. Hrd1 is generally viewed as being a member of the adaptive UPR gene programme, since it is involved in removing toxic misfolded proteins from the ER (Figure 1D). However, in the report by Yang et al.,⁵ Hrd1 is maladaptive, as it increases the rate of degradation of an adaptive transcription factor, Nrf2. So, one of the mechanistic questions that arise is, can an ER stress-inducible protein, like Hrd1, be both adaptive and maladaptive at the same time? If so, as must be the case in this report, what regulates whether it behaves adaptively or maladaptively? For example, with Hrd1, is it possible that it behaves adaptively, by degrading misfolded toxic ER proteins, at the same time as maladaptively, by degrading Nrf2? And what dictates which of the two effects of Hrd1 dominate?

Like many pre-clinical studies, the work of Yang et al.⁵ leads to additional questions. Does tirzepatide also decrease maladaptive ER stress in tumour cells? If so, this might limit the clinical utility of tirzepatide during Dox treatment, as well as other anti-cancer drugs that reduce ER stress. In support of this, retrospective studies have reported that incretin mimetic administration is associated with an increased risk of pacreatitis and pancreatic cancer.⁹ How does tirzepatide work directly on isolated cardiac myocytes to reduce ER stress and is it the same mechanism of action that results in cardioprotection, in vivo? Cardiac myocytes have incretin receptors so presumably, agonists of these receptors activate adaptive signalling in cardiac myocytes. Indeed, previous studies have shown that tirzepatide acts on isolated cardiac myocytes to reduce the maladaptive effects of high glucose media on induction of cardiac pathology gene expression.¹⁰ Since the adaptive UPR depends on Hrd1/ERAD-mediated degradation of toxic misfolded ER proteins and since tirzepatide decreases Hrd1, at least in the heart, might long-term use of it be maladaptive, in that it would reduce ERAD-mediated degradation of toxic misfolded proteins? Also, insulin production by β-cells of the pancreas relies on a robust UPR and Hrd1-dependent degradation of misfolded toxic insulin. Might long-term use of tirzepatide actually be maladaptive in β-cells and perhaps other pancreatic endocrine cells, such as to compromise their ability to degrade misfolded proteotoxic ER proteins?

These questions suggest that much is yet to be learned regarding the broad effects of tirzepatide and other incretin hormone mimetics. While its effects on weight gain have proven to be life changing for many patients, much remains to be understood about additional effects of incretin hormone–based therapeutics in health and disease.