Although many animal studies indicate insulin has cardioprotective effects, clinical studies suggest a link between insulin resistance (hyperinsulinemia) and heart failure (HF). Here we have demonstrated that excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents. Chronic pressure overload induced hepatic insulin resistance and plasma insulin level elevation. In contrast, cardiac insulin signaling was upregulated by chronic pressure overload because of mechanical stretch–induced activation of cardiomyocyte insulin receptors and upregulation of insulin receptor and Irs1 expression. Chronic pressure overload increased the mismatch between cardiomyocyte size and vascularity, thereby inducing myocardial hypoxia and cardiomyocyte death. Inhibition of hyperinsulinemia substantially improved pressure overload–induced cardiac dysfunction, improving myocardial hypoxia and decreasing cardiomyocyte death. Likewise, the cardiomyocyte-specific reduction of insulin receptor expression prevented cardiac ischemia and hypertrophy and attenuated systolic dysfunction due to pressure overload. Conversely, treatment of type 1 diabetic mice with insulin improved hyperglycemia during pressure overload, but increased myocardial ischemia and cardiomyocyte death, thereby inducing HF. Promoting angiogenesis restored the cardiac dysfunction induced by insulin treatment. We therefore suggest that the use of insulin to control hyperglycemia could be harmful in the setting of pressure overload and that modulation of insulin signaling is crucial for the treatment of HF.
Ippei Shimizu, Tohru Minamino, Haruhiro Toko, Sho Okada, Hiroyuki Ikeda, Noritaka Yasuda, Kaoru Tateno, Junji Moriya, Masataka Yokoyama, Aika Nojima, Gou Young Koh, Hiroshi Akazawa, Ichiro Shiojima, C. Ronald Kahn, E. Dale Abel, Issei Komuro
Submitter: Wenjun Yan | fgao@fmmu.edu.cn
Authors: Peilin Liu, Wenjuan Xing, Xiaoqing Cai, Jun Li, Haifeng Zhang, and Feng Gao
Department of Physiology and Department of Cardiology, Xijing Hospital, Fourth Military Medical University
Published May 5, 2010
To the Editor: In the article by Shimizu et al [1], the authors found that chronic pressure overload increases the mismatch between cardiomyocyte size and vascularity, thus leading to systolic dysfunction by activating cardiac insulin signaling, and concluded that the sustained activation of insulin/Akt contributes to these adverse cardiac changes. However, from their data we infer that it is insulin/MAPK, but not insulin/Akt signaling that is at play.
Accumulating evidence has shown that insulin/Akt signaling plays a crucial role in the development of physiological hypertrophy as well as in normal cardiac growth, whereas insulin/MAPK signaling contributes to pathological hypertrophy [2-5]. In this article, the data clearly indicated that pressure overload causes cardiac hypertrophy and reduces vascular density in cardiomyocyte-specific insulin receptor knockout (CIRKO) mice (Figure 5B and 5C; Figure 4C and 4D; CIRKO+TAC vs. CIRKO+Sham), which was consistent with previous study [6]. In addition, the CIRKO+TAC mice showed increased phosphorylation of Irs1 and MAPK (Figure 4B: Relative pIrs1 and pMAPK level) and unchanged phosphorylation of Akt (Figure 4B: Relative pAkt level) compared with those in CIRKO+Sham mice. These data suggest that the increased insulin/MAPK signaling rather than insulin/Akt contributes to the mismatch between cardiomyocyte size and vascularity in CIRKO+TAC cardiac structural change induced by pressure overload. This is also strongly supported by the authors’ findings that unchanged systolic function but increased cardiomyocyte size and decreased vascular density in Akt1+/–mice (Figure 6A and 6C; Akt1+/– +TAC vs. Akt1+/– +Sham). More importantly, although there was increased myocardial Akt expression, their data showed that the pAkt level was not increased in Akt1+/– +TAC mice (Figure 6D: Akt1+/– +TAC vs. Akt1+/– +Sham).
Taken together, these results suggest that it is insulin/MAPK signaling, but not insulin/Akt, that contributes directly to the pressure overload-induced cardiac structural change in mice. Further study on the role of insulin/MAPK signaling in pressure overload may provide important information on pathologic cardiac hypertrophy.
No conflicts of interest are declared by the authors.
Submitter: Feng Fu | fgao@fmmu.edu.cn
Authors: Xiaoqing Cai, Lele Ji, Heng Ma, Jia Li, and Feng Gao
Department of Physiology and Department of Cardiology, Xijing Hospital, Fourth Military Medical University
Published May 4, 2010
To the Editor: In the article by Shimizu et al (1), they found that chronic pressure overload induced hyperinsulinemia, upregulation of cardiac insulin signaling and left ventricular systolic dysfunction 2 weeks after transverse aortic constriction (TAC). Surprisingly, inhibition of cardiac insulin signaling by either STZ treatment or cardiomyocyte-specific insulin receptor knockout (CIRKO) attenuated systolic dysfunction induced by TAC. We beg to differ.
Ample evidence have demonstrated that STZ is a pro-apoptotic and cytotoxic agent which could cause damage to the heart (2). And nearly all the studies published so far with CIRKO mice have shown that selective knockout of the myocardial insulin receptor leave animals vulnerable to additional insults such as myocardial ischemia and increased afterload (3, 4), including accelerated systolic dysfunction during cardiac pressure overload (4). These data suggest that impaired insulin signaling may aggravate cardiac injury. On the other hand, our previous study found that insulin treatment reduced ischemic myocardial injury and improved prolonged post-ischemic cardiac function (5, 6). Moreover, the present study also showed (in Figure 3D) that the left ventricular cavity in TAC heart with STZ plus insulin was smaller than that in TAC heart, indicating that insulin may have benefinial effects on cardiac function in TAC mice. Thus, an additional group of TAC with insulin treatment would provide more strong evidence.
Taken together, these results indicate that the impaired insulin signaling may aggravate cardiac injury, whereas excessive cardiac insulin signaling may be just a compensatory response rather than the cause for the systolic dysfunction induced by pressure overload.
We declare that we have no conflict of interest.