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Hypertension and Diabetes Cooperatively Drive HSP90 Activation, HSP70 Suppression, and Left Ventricular Interstitial
Anastasia P Sklifasovskaya1, Mikhail L Blagonravov1, Madina M Azova1
1Institute of Medicine, RUDN University, 6 Miklukho-Maklaya St., Moscow 117198, Russia.
Insights
Combined arterial hypertension (AH) and diabetes mellitus (DM) synergistically increase HSP90 and suppress HSP70 in the heart, suggesting a maladaptive stress response driving cardiac damage.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Stress Response Mechanisms
Background:
- Arterial hypertension (AH) and insulin-dependent diabetes mellitus (DM) are significant risk factors for myocardial damage.
- The combined effects of AH and DM on heat shock proteins (HSP70, HSP90) in the heart remain poorly understood.
- Investigating these stress proteins is crucial for understanding accelerated cardiac remodeling in comorbid conditions.
Purpose of the Study:
- To characterize HSP70 and HSP90 expression in left ventricular cardiomyocytes under isolated and combined AH and DM.
- To evaluate the association of HSP expression with myocardial structural remodeling and interstitial expansion.
- To elucidate the cellular stress response in comorbid cardiometabolic disease.
Main Methods:
- Utilized a rat model with five groups: control, isolated AH, long-term AH, isolated DM, and combined AH+DM.
- Analyzed left ventricular tissue using immunohistochemistry for HSP70/HSP90 protein and RT-qPCR for mRNA levels.
- Quantified interstitial stromal volume fraction via morphometry on H&E-stained sections.
Main Results:
- HSP90 was upregulated in all pathological groups, most significantly in isolated DM and AH+DM.
- HSP70 protein increased in AH but decreased significantly in the AH+DM group.
- Combined AH+DM showed the most severe interstitial expansion, indicating significant myocardial remodeling.
Conclusions:
- Comorbid AH and DM induce synergistic HSP90 upregulation and HSP70 suppression, shifting the cellular response to a maladaptive state.
- This HSP imbalance is a potential key mechanism for accelerated myocardial deterioration in cardiometabolic comorbidity.
- Targeting HSP pathways could offer therapeutic strategies for managing comorbid cardiovascular and metabolic diseases.
Background:
Arterial hypertension (AH) and insulin-dependent diabetes mellitus (DM) are major comorbid risk factors for accelerated myocardial damage, yet the behavior of key stress-adaptive heat shock proteins HSP70 and HSP90 under combined stress remains unclear. This study aimed to characterize the expression profiles of HSP70 and HSP90 in left ventricular cardiomyocytes during isolated and comorbid AH and DM, and to evaluate their association with structural remodeling and expansion of interstitial elements.
Methods:
The study was conducted in accordance with the European Convention for the Protection of Vertebrate Animals (ethical approval No. 26, RUDN Institute of Medicine, 18 February 2021) on 25 male rats divided into five groups (n = 5 each): control-38-week-old Wistar-Kyoto (WKY) rats; AH-38-week-old spontaneously hypertensive rats (SHR); long-term AH-57-week-old SHR; DM-38-week-old WKY rats with streptozotocin-induced insulin-dependent DM (65 mg/kg, i.p.); AH+DM-38-week-old SHR with STZ-induced DM. After 30 days of DM, left ventricular (LV) tissue was analyzed by immunohistochemistry (IHC) for HSP70/HSP90 protein expression and by RT-qPCR for mRNA levels. Increased stromal elements in myocardium were quantified morphometrically as interstitial stromal volume fraction (%) on hematoxylin and eosin-stained sections.
Results:
HSP90 was significantly upregulated in all pathological groups. The most pronounced increase occurred in isolated DM, with a 4.0-fold rise in HSP90-positive area (21.80% vs. 5.45% in control) and a 1.82-fold increase in mRNA. In the AH+DM group, HSP90 mRNA expression was extremely elevated (25.93-fold), accompanied by a 3.7-fold increase in protein. In contrast, HSP70 protein was elevated only in the 38-week AH group (27.68% vs. 19.70% control, p ≤ 0.05), remained unchanged in isolated DM (19.50%), and was significantly reduced in AH+DM (14.71%, p ≤ 0.05), despite a modest 1.64-fold mRNA upregulation in DM. Morphometric analysis revealed progressive expansion of interstitial elements, most severe in AH+DM (9.43% stromal volume vs. 4.81% in control, p ≤ 0.05).
Conclusions:
Comorbid AH and DM provoke synergistic HSP90 upregulation, while HSP70 expression is markedly suppressed, indicating a shift from an adaptive to a maladaptive cellular-stress response. The imbalance between HSP90 and HSP70 may represent a key molecular mechanism underlying accelerated structural and functional deterioration of the myocardium in cardiometabolic comorbidity.
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